Non-Systemic Topical Compositions Comprising Corticosteroids

ABSTRACT

Described herein are topical, non-systemic, slow releasing oral pharmaceutical compositions, methods for making the same, and methods for treating subjects in need thereof with such compositions. In particular, the oral composition provides topical, non-systemic administration of one or more active pharmaceutical ingredients to the oral cavity and upper gastrointestinal track, including the esophagus. In one embodiment, the pharmaceutical composition provides topical corticosteroids to the esophagus and oral cavity.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation in part of U.S. patent applicationSer. No. 15/181,462 and International Patent Application No.PCT/US2016/3732, both filed on Jun. 14, 2016, and both which claimpriority to U.S. Provisional Patent Application No. 62/175,470, filed onJun. 15, 2015, each of which is incorporated by reference herein in itsentirety.

TECHNICAL FIELD

Described herein are oral pharmaceutical compositions suitable forchewing, sucking, buccal dissolution, or swallowing comprisingnon-systemic corticosteroids soft lozenges, and methods for treatingsubjects in need thereof with such compositions. In particular, the oralcomposition provides topical, non-systemic administration andslow-release of one or more active pharmaceutical ingredients to theoral cavity and upper gastrointestinal track, including the esophagus.

BACKGROUND

Steroid therapy has long been the therapy of choice for reducinginflammation by the application of a topical corticosteroid to theaffected area, such as in the case of eczema, asthma, or other allergicconditions. In order to reduce systemic toxicity associated with steroiduse, topical preparations were developed for inflammation disorders ofthe esophagus or gastrointestinal tract, such that the steroid couldadhere to the esophageal mucosa and provide an anti-inflammatory effect.However, topical corticosteroid therapy is limited. For these types ofdisorders, treatments have typically involved patients swallowinginhaled corticosteroid medications or corticosteroid suspensions.Treatment using inhaled corticosteroids is achieved via a “puff andswallow” technique, where the patient administers the corticosteroidcomposition to the mouth, but swallows rather than inhaling. Thistechnique is often difficult for children and geriatric patients, andcan result in variable doses and less than an effective dose of thesteroid being delivered to the esophagus. In addition, oraladministration of topical steroids can also result in oropharyngeal oresophageal candidosis.

Thus, there is an unmet need for oral dosage forms of corticosteroids,where the dosage form can be chewed, sucked, permitted to dissolve inthe mouth, or swallowed, and has desirable organoleptic properties;slowly releases the active ingredient in the oral cavity and esophagus;and maintains drug contact with the oral and esophageal tissue for anextended period providing topical, non-systemic delivery.

SUMMARY

Described herein are pharmaceutical compositions containing one or moreactive ingredients intended to dissolve or disintegrate slowly in theoral cavity. They can be used for topical treatment where the drug isnot absorbed through the buccal or esophageal lining. In particular,soft lozenges can be chewed or allowed to dissolve slowly in the mouth.These dosage forms can be flavored and thus are administrable to bothpediatric and geriatric patients; they can deliver limited quantities ofthe active ingredient to the oral cavity and upper gastric system withminimal systemic adsorption; and they allow for the drug to remain incontact with the oral cavity or esophagus for an extended period oftime. Soft lozenges or liquid compositions comprising corticosteroidsfacilitate the topical, non-systemic delivery of corticosteroids fortreating esophageal inflammation disorders.

One embodiment described herein is a topical, non-systemic, oral, slowreleasing pharmaceutical composition comprising: (a) about 1% to about5% by mass of one or more release modifiers; (b) about 10% to about 60%by mass of one or more film-forming polymers; (c) about 5% to about 20%by mass of one or more plasticizers; and (d) less than 1% by mass of oneor more active pharmaceutical ingredients. In one aspect, thecomposition, further comprises: (e) about 0.1% to about 5% by mass ofone or more pH modifiers; (f) about 10% to about 80% by mass of one ormore sweeteners; and (g) about 5% to about 30% by mass of one or moresolvents. In another aspect, the composition, further comprises: (h) oneor more opacifiers, coloring agent, flavoring, thickening agents orcombinations thereof; (i) one or more solubilizing agents; and (j) oneor more second active pharmaceutical ingredients. In another aspect, thecomposition comprises a soft lozenge. In another aspect, the compositioncomprises a liquid. In another aspect, the composition orally dissolveswithin about 10 to about 15 minutes upon administration to a subject. Inanother aspect, the composition achieves about 50% dissolution in vitroat pH 7.4 within about 10 to about 30 minutes. In another aspect, thecomposition topically contacts the oral and esophageal mucosa for atleast about 1 minute to about 45 minutes. In another aspect, thecomposition topically contacts the oral and esophageal mucosa for atleast about 1 minute to about 15 minutes. In another aspect, the releasemodifier comprises one or more of polyethylene oxide, methylcellulose,hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethylcellulose, hydroxymethyl cellulose, polymethylmethacrylate,polyhydroxyethylmethacrylate, polyvinylpyrrolidone, copovidone,polyvinyl alcohol, copolymers of polyvinylpyrrolidone and polyvinylacetate, or combinations thereof. In another aspect, the releasemodifier comprises polyethylene oxide. In another aspect, the releasemodifier comprises polyethylene oxide having a molecular weight (M_(v))of about 900,000 to about 8,000,000. In another aspect, the releasemodifier comprises polyethylene oxide having a molecular weight (M_(v))of about 7,000,000. In another aspect, the film-forming polymercomprises one or more of gelatin, partially hydrolyzed gelatin,hydrolyzed gelatin, hydrolyzed collagen, or combinations thereof. Inanother aspect, the film-forming polymer comprises one or more gelatins,having a Bloom value of about 50 Bloom to about 150 Bloom. In anotheraspect, the plasticizer comprises one or more of glycerol, sorbitol,mannitol, maltitol, xylitol, or combinations thereof. In another aspect,the pH modifier comprises one or more of citric acid, acetic acid,lactic acid, malic acid, tartaric acid, fumaric acid, or combinationsthereof. In another aspect, the sweetener comprises one or more ofxylitol, maltitol, sucralose, mannitol aspartame, stevia, orcombinations thereof. In another aspect, the solubilizing agentcomprises poloxamer, polyoxyethylene 50 stearate, polyoxyl 35 castoroil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether,polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20,polysorbate 40, polysorbate 60, polysorbate 80, propylene glycoldiacetate, propylene glycol monostearate, sodium lauryl sulfate, sodiumstearate, sorbitan monolaurate, sorbitan monooleate, sorbitanmonopalmitate, sorbitan monostearate, or combinations thereof. Inanother aspect, the thickening agent comprises polyacrylic acid, methylcellulose, alginic acid, chitosan, carboxymethyl cellulose, sodiumcarboxymethyl cellulose, locust bean gum, xanthum gum, high swellingcrosslinked polymers, or combinations thereof. In another aspect, theactive pharmaceutical ingredient comprises one or more corticosteroids.In another aspect, the active pharmaceutical ingredient comprises one ormore of alclometasone, amcinonide, beclometasone, betamethasone,budesonide, ciclesonide, clobetasol, clobetasone, clocortolone,cloprednol, cortivazol, deflazacort, deoxycorticosterone, desonidedesoximetasone, dexamethasone, diflorasone, diflucortolone,difluprednate, fluclorolone, fludrocortisone, fludroxycortide,flumetasone, flunisolide, fluocinolone acetonide, fluocinonide,fluocortin, fluocortolone, fluorometholone, fluperolone, fluticasone,fluticasone propionate, fluprednidene, formocortal, halcinonide,halometasone, hydrocortisone aceponate, hydrocortisone buteprate,hydrocortisone butyrate, loteprednol, medrysone, meprednisone,methylprednisolone, methylprednisolone aceponate, mometasone furoate,paramethasone, prednicarbate, prednisone, prednisolone, prednylidene,rimexolone, tixocortol, triamcinolone, ulobetasol, combinations thereof,pharmaceutically acceptable salts thereof, or esters thereof. In anotheraspect, the active pharmaceutical ingredients comprise one or more offluticasone, budesonide, salts thereof, or combinations thereof. Inanother aspect, the active pharmaceutical ingredient comprisesfluticasone or a salt thereof. In another aspect, the activepharmaceutical ingredient comprises fluticasone propionate. In anotheraspect, the composition comprises about 0.025% or about 0.05%fluticasone propionate. In another aspect, the composition comprisesabout 0.5 mg or about 1.0 mg of fluticasone propionate. In anotheraspect, the second active pharmaceutical ingredient comprises lidocaine,prilocaine, or a combination thereof. In another aspect, the compositiontopically contacts the oral and esophageal mucosa for about 1 minute toabout 10 minutes.

Another embodiment described herein is topical, non-systemic oralpharmaceutical composition comprising: (a) about 10% to about 60% bymass of one or more film-forming polymers; (b) about 5% to about 20% bymass of one or more plasticizers; (c) about 0.1% to about 5% by mass ofone or more pH modifiers; (d) about 10% to about 80% by mass of one ormore sweeteners; (e) about 5% to about 30% by mass of one or moresolvents; and (g) about 1% to about 5% by mass of one or more releasemodifiers; (h) about 0.1% to about 5% by mass of one or moresolubilizing agents; and (i) about 0.001% to about 1% by mass offluticasone propionate. In one aspect, the composition further comprises(j) about 0.1% to about 50% by mass of one or more thickening agents. Inanother aspect, the composition further comprises a second activepharmaceutical ingredient. In another aspect, the second activepharmaceutical ingredient comprises about 0.5% to about 5% by weight oflidocaine, prilocaine, or a combination thereof, and the weightpercentage of maltitol is reduced accordingly. In another aspect, thecomposition comprises a liquid or solid dosage form. In another aspect,the liquid dosage form comprises a solution, syrup, suspension, elixir,or concentrate. In another aspect, the solid dosage form comprises asoft lozenge. In another aspect, the composition orally dissolves withinabout 10 to about 15 minutes upon administration to a subject. Inanother aspect, the composition achieves 50% dissolution in vitro at pH7.4 within about 10 to about 30 minutes. In another aspect, thecomposition topically contacts the oral and esophageal mucosa for atleast about 1 minute to about 45 minutes. In another aspect, thecomposition provides one or more of the following pharmacokineticparameters upon administration to a subject: (a) a mean plasmafluticasone propionate T_(max) of about 1.75 hours to about 3 hours; (b)a mean plasma fluticasone propionate C_(max) of about 8 pg/mL to about11 pg/mL; (c) a mean plasma fluticasone propionate AUC_(0→τ), of about105 pg·h/mL to about 130 pg·h/mL; (d) a mean plasma fluticasonepropionate AUC_(0→∞) of about 150 pg·h/mL to about 160 pg·h/mL; (e) amean fluticasone propionate half-life (t_(1/2)) of about 0.01 h to about0.1 h; or (f) a mean fluticasone terminal elimination rate constant (λ)of about 10 h⁻¹ to about 20 h⁻¹. In another aspect, the composition isuseful for treating a subject suffering from one or more of oral oresophageal inflammation, eosinophilic esophagitis, inflammatory boweldisease involving the esophagus, oral lichen planus, aphthousstomatitis, Crohn's disease, esophageal inflammation secondary tocaustic/irritant ingestion, recurrent esophageal strictures of any causeand including irritant ingestion, pill-induced esophagitis, systemicdiseases, congential diseases, epidermolysis bullosa, trauma, orpost-surgery inflammation.

Another embodiment described herein is a method for treating, retardingthe progression of, prophylaxis of, delaying the onset of, ameliorating,or reducing the symptoms of one or more of esophageal, oral, or buccalinflammation, eosinophilic esophagitis, oral lichen planus, aphthousstomatitis, odynophagia, acid reflux, dysphagia, oral, esophageal orpeptic ulcers, heart burn, chest pain, abdominal pain, nausea, vomiting,coughing, sore throat, decrease in appetite, or failure to thrive,comprising administering to a subject in need thereof any of thepharmaceutical compositions described herein.

Another embodiment described herein is a pharmaceutical compositionuseful for retarding the progression of, prophylaxis of, delaying theonset of, ameliorating, or reducing the symptoms of one or more ofesophageal, oral, or buccal inflammation, eosinophilic esophagitis, orallichen planus, aphthous stomatitis, odynophagia, acid reflux, dysphagia,oral, esophageal or peptic ulcers, heart burn, chest pain, abdominalpain, nausea, vomiting, coughing, sore throat, decrease in appetite, orfailure to thrive, comprising administering to a subject in need thereofany of the pharmaceutical compositions described herein.

Another embodiment described herein is a method for treating fortreating, retarding the progression of, prophylaxis of, delaying theonset of, ameliorating, or reducing the symptoms of one or more ofesophageal oral, or buccal inflammation, eosinophilic esophagitis,inflammatory bowel disease involving the esophagus, oral lichen planus,aphthous stomatitis, Crohn's disease, esophageal inflammation secondaryto caustic/irritant ingestion, recurrent esophageal strictures of anycause and including irritant ingestion, pill-induced esophagitis,systemic diseases, congential diseases, epidermolysis bullosa, trauma,or post-surgery inflammation comprising administering to a subject inneed thereof any of the pharmaceutical compositions described herein. Inone aspect, the composition provides one or more of the followingpharmacokinetic parameters: (a) a mean plasma fluticasone propionateT_(max) of about 1.75 hours to about 3 hours; (b) a mean plasmafluticasone propionate C_(max) of about 8 pg/mL to about 11 pg/mL; (c) amean plasma fluticasone propionate AUC_(0→τ) of about 105 pg·h/mL toabout 130 pg·h/mL; (d) a mean plasma fluticasone propionate AUG_(0→∞) ofabout 150 pg·h/mL to about 160 pg·h/mL; (e) a mean fluticasonepropionate half-life (t_(1/2)) of about 0.01 h to about 0.1 h; or (f) amean fluticasone terminal elimination rate constant (λ) of about 10 h⁻¹to about 20 h⁻¹.

Another embodiment described herein is a pharmaceutical combinationcomprising the one of the compositions described herein comprising acorticosteroid and one or more additional therapeutic compounds. In oneaspect, the one or more additional therapeutic compound comprises one ormore of antacids (e.g., calcium hydroxide, magnesium hydroxide,alluminum hydroxide, sodium bicarbonate, calcium carbonate, bismuthsubsalicylate, or others; Maalox, Mylanta, Gaviscon, Kaopectate,Pepto-Bismol) sucralfate, esomeprazole, omeprazole, lansoprazole,dexlansoprazole, esomeprazole, pantoprazole, rabeprazole, ilaprazole,cimetidine, ranitidine, famotidine, lafutidine, nizatidine, roxatidine,tiotidine, salmeterol, albuterol, aclidinium, ipratropium, tiotropium,umeclidinium, acrivastine, azelastine, bilastine, brompheniramine,buclizine, bromodiphenhydramine, carbinoxamine, chlorpromazine,cyclizine, chlorphenamine, chlorodiphenhydramine, clemastine,cyproheptadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate,dimetindene, diphenhydramine, doxylamine, ebastine, embramine,fexofenadine, hydroxyzine, loratadine, meclozine, mirtazapine,olopatadine, orphenadrine, phenindamine pheniramine, phenyltoloxamine,promethazine, quetiapine, rupatadine, tripelennamine, triprolidine,clobenpropit, ciproxifan, conessine, thioperamide, montelukast,zafirlukast, pranlukast, mepolizumab, reslizumab, omalizumab,infliximab, azathioprine, 6-mercaptopurine, thioguanine, aspirin(acetylsalicylic acid), ibuprofen, naproxen, ketoprofen, celecoxib,diclofenac, amikacin, gentamicin, kanamycin, neomycin, netilmicin,tobramycin, paromomycin, streptomycin, spectinomycin, geldanamycin,herbimycin, rifaximin, loracarbef, ertapenem, doripenem,imipenem/cilastatin, meropenem, cefadroxil, cefazolin, cefalotin,cefalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime,cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime,ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftarolinefosamil, ceftobiprole, teicoplanin, vancomycin, telavancin, dalbavancin,oritavancin, clindamycin, lincomycin, daptomycin, azithromycin,clarithromycin, dirithromycin, erythromycin, roxithromycin,troleandomycin, telithromycin, spiramycin, aztreonam, furazolidone,nitrofurantoin, linezolid, posizolid, radezolid, torezolid, amoxicillin,ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin,flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin,penicillin G, penicillin V, piperacillin, temocillin, ticarcillin,amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam,ticarcillin/clavulanate, bacitracin, colistin, polymyxin B,ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin,lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin,trovafloxacin, grepafloxacin, sparfloxacin, temafloxacin, mafenide,sulfacetamide, sulfadiazine, silver sulfadiazine, sulfadimethoxine,sulfamethizole, sulfamethoxazole, sulfanilimide, sulfasalazine,sulfisoxazole, trimethoprim-sulfamethoxazole, sulfamidochrysoidine,demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline,clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide,isoniazid, pyrazinamide, rifampicin, rifabutin, rifapentine,streptomycin, arsphenamine, chloramphenicol, fosfomycin, fusidic acid,metronidazole, mupirocin, platensimycin, quinupristin/dalfopristin,thiamphenicol, tigecycline, tinidazole, trimethoprim, or combinationsthereof.

One embodiment described herein comprises a topical, non-systemic oralsoft lozenge pharmaceutical composition comprising a shell encapsulatinga semi solid matrix fill, the shell comprising: (a) one or more firstfilm-forming polymers; (b) one or more first plasticizers; (c) one ormore first pH modifiers; (d) one or more first sweeteners; and (e) oneor more first solvents; and the matrix fill comprising: (f) one or moresecond film-forming polymers; (g) one or more release modifiers; (h) oneor more second plasticizers; (i) one or more second pH modifiers; (j)one or more second sweeteners; (k) one or more second solvents; and (l)one or more active pharmaceutical ingredients. In one aspect, the shellfurther comprises: (m) one or more opacifiers, coloring agents,flavorings, or combinations thereof; and the matrix comprises: (n) oneor more solubilizing agents; and (o) one or more second activepharmaceutical ingredients. In another aspect, the shell or matrixfurther comprises one or more pharmaceutically acceptable excipients. Inanother aspect, the film-forming polymer comprises one or more ofgelatin, partially hydrolyzed gelatin, hydrolyzed gelatin, hydrolyzedcollagen, or combinations thereof. In another aspect, the film-formingpolymer comprises one or more gelatins, having a Bloom value of about 50Bloom to about 150 Bloom. In another aspect, the plasticizer comprisesone or more of glycerol, sorbitol, mannitol, maltitol, xylitol, orcombinations thereof. In another aspect, the pH modifier comprises oneor more of citric acid, acetic acid, lactic acid, malic acid, tartaricacid, fumaric acid, or combinations thereof. In another aspect, therelease modifier comprises one or more of polyethylene oxide,methylcellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxymethyl cellulose, polymethylmethacrylate,polyhydroxyethylmethacrylate, polyvinylpyrrolidone, copovidone,polyvinyl alcohol, copolymers of polyvinylpyrrolidone and polyvinylacetate, or combinations thereof. In another aspect, the releasemodifier comprises polyethylene oxide. In another aspect, the releasemodifier comprises polyethylene oxide having a molecular weight (M_(v))of about 900,000 to about 8,000,000. In another aspect, the releasemodifier comprises polyethylene oxide having a molecular weight (M_(v))of about 7,000,000. In another aspect, the sweetener comprises one ormore of xylitol, maltitol, sucralose, mannitol aspartame, stevia, orcombinations thereof. In another aspect, the solubilizing agentcomprises poloxamer, polyoxyethylene 50 stearate, polyoxyl 35 castoroil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether,polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20,polysorbate 40, polysorbate 60, polysorbate 80, propylene glycoldiacetate, propylene glycol monostearate, sodium lauryl sulfate, sodiumstearate, sorbitan monolaurate, sorbitan monooleate, sorbitanmonopalmitate, sorbitan monostearate, or combinations thereof. Inanother aspect, the active pharmaceutical ingredient comprises one ormore corticosteroids or glucocorticosteroids. The composition of claim1, wherein the active pharmaceutical ingredient comprises one or more ofalclometasone, amcinonide, beclometasone, betamethasone, budesonide,ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol,cortivazol, deflazacort, deoxycorticosterone, desonide desoximetasone,dexamethasone, diflorasone, diflucortolone, difluprednate, fluclorolone,fludrocortisone, fludroxycortide, flumetasone, flunisolide, fluocinoloneacetonide, fluocinonide, fluocortin, fluocortolone, fluorometholone,fluperolone, fluticasone, fluticasone propionate, fluprednidene,formocortal, halcinonide, halometasone, hydrocortisone aceponate,hydrocortisone buteprate, hydrocortisone butyrate, loteprednol,medrysone, meprednisone, methylprednisolone, methylprednisoloneaceponate, mometasone furoate, paramethasone, prednicarbate, prednisone,prednisolone, prednylidene, rimexolone, tixocortol, triamcinolone,ulobetasol, combinations thereof, pharmaceutically acceptable saltsthereof, or esters thereof. In another aspect, the active pharmaceuticalingredients comprise one or more of fluticasone, budesonide, saltsthereof, or combinations thereof. In another aspect, the activepharmaceutical ingredient comprises fluticasone or a salt thereof. Inanother aspect, the active pharmaceutical ingredient comprisesfluticasone propionate. In another aspect, the matrix comprises about0.025% or about 0.05% fluticasone. In another aspect, the matrixcomprises about 0.5 mg or about 1.0 mg of fluticasone. In anotheraspect, the second active pharmaceutical ingredient comprises lidocaine,prilocaine, or a combination thereof.

Another embodiment described herein comprises a pharmaceuticalcomposition comprising a shell encapsulating a semi solid matrix fill,wherein the shell comprises: (a) about 10% to about 60% of one or morefirst film-forming polymers; (b) about 5% to about 20% of one or morefirst plasticizers; (c) about 0.1% to about 5% of one or more first pHmodifiers; (d) about 10% to about 80% of one or more first sweeteners;and (e) about 5% to about 30% of one or more first solvents; and thematrix comprises: (f) about 5% to about 30% of one or more secondfilm-forming polymers; (g) about 1% to about 5% of one or more releasemodifiers; (h) about 5% to about 20% of one or more second plasticizers;(i) about 0.5% to about 5% of one or more second pH modifiers; (j) about10% to about 80% of one or more second sweeteners; (k) about 0.1% toabout 5% of one or more solubilizing agents; (l) about 5% to about 30%of one or more second solvents; and (m) about 0.001% to about 1% of oneor more active pharmaceutical ingredients.

Another embodiment described herein comprises a pharmaceuticalcomposition comprising a shell encapsulating a semi solid matrix fill,wherein the shell comprises: (a) about 34% of one or more firstfilm-forming polymers; (b) about 23% of one or more first plasticizers;(c) about 0.5% of one or more first pH modifiers; (d) about 17% of oneor more first sweeteners; and (e) about 25% of one or more firstsolvents; and the matrix comprises: (f) about 7.5% of one or more secondfilm-forming polymers; (g) about 3.0% of one or more release modifiers;(h) about 7.5% of one or more second plasticizers; (i) about 1% of oneor more second pH modifiers; (j) about 62% of one or more secondsweeteners; (k) about 0.7% of one or more solubilizing agents; (l) about18% of one or more second solvents; and (m) about 0.025% or about 0.05%of one or more active pharmaceutical ingredients.

Another embodiment described herein comprises a pharmaceuticalcomposition comprising (a) about 15% to about 20% of one or morefilm-forming polymers; (b) about 0.5% to about 3% of one or more releasemodifiers; (c) about 10% to about 15% of one or more plasticizers; (d)about 0.5% to about 1.5% of one or more pH modifiers; (e) about 40% toabout 55% of one or more sweeteners; (f) about 0.1% to about 1% of oneor more solubilizing agents; (g) about 15% to about 25% of one or moresolvents; (h) about 0.01% or about 0.1% of one or more activepharmaceutical ingredients; and (i) optionally, about 0.1% to about 1%of one or more excipients comprising opacifiers, colorings, orflavorings.

Another embodiment described herein comprises a pharmaceuticalcomposition comprising (a) about 17% of one or more film-formingpolymers; (b) about 2% of one or more release modifiers; (c) about 13%of one or more plasticizers; (d) about 0.8% of one or more pH modifiers;(e) about 46% of one or more sweeteners; (f) about 0.4% of one or moresolubilizing agents; (g) about 20% of one or more solvents; (h) about0.016% or about 0.032% of one or more active pharmaceutical ingredients;and (i) optionally, about 0.5% of one or more excipients comprisingopacifiers, colorings, or flavorings.

Another embodiment described herein comprises a pharmaceuticalcomposition comprising a shell encapsulating a semi solid matrix fill,wherein the shell comprises: (a) about 5% to about 30% of 150 Bloomgelatin; (b) about 5% to about 20% of 100 Bloom gelatin; (c) about 1% toabout 10% of gelatin hydrolysate; (d) about 5% to about 30% of glycerol;(e) about 0.1% to about 5% of citric acid; (f) about 5% to about 30% ofmaltitol; (g) about 1% to about 10% of xylitol; (h) about 0.1% to about2% of sucralose; and (i) about 5% to about 30% of water; and the matrixcomprises: (j) about 5% to about 20% of 150 Bloom gelatin; (k) about 1%to about 5% of polyethylene oxide; (l) about 5% to about 10% ofglycerol; (m) about 0.5% to about 5% of citric acid; (n) about 30% toabout 65% of maltitol; (o) about 1% to about 10% of xylitol; (p) about0.1% to about 2% of sucralose; (q) about 0.1% to about 1% of polysorbate80; (r) about 10% to about 30% of water; and (s) about 0.001% to about1% of fluticasone propionate.

Another embodiment described herein comprises a pharmaceuticalcomposition comprising a shell encapsulating a semi solid matrix fill,the shell comprises: (a) about 19% 150 Bloom gelatin; (b) about 13% 100Bloom gelatin; (c) about 2.5% gelatin hydrolysate; (d) about 23%glycerol; (e) about 0.5% citric acid; (f) about 14% maltitol; (g) about2.5% xylitol; (h) about 0.2% sucralose; and (i) about 25% water; and thematrix comprises: (j) about 7.5% 150 Bloom gelatin; (k) about 3%polyethylene oxide; (l) about 5% to about 10% of glycerol; (m) about 1%citric acid; (n) about 58% maltitol; (o) about 4% of xylitol; (p) about0.3% sucralose; (q) about 0.7% polysorbate 80; (r) about 18% water; and(s) about 0.025% or about 0.05% fluticasone propionate.

Another embodiment described herein comprises a pharmaceuticalcomposition comprising (a) about 5% to about 30% of 150 Bloom gelatin;(b) about 5% to about 20% of 100 Bloom gelatin; (c) about 1% to about10% of gelatin hydrolysate; (d) about 1% to about 5% of polyethyleneoxide; (e) about 1% to about 20% of glycerol; (f) about 0.1% to about 5%of citric acid; (g) about 20% to about 60% of maltitol; (h) about 0.5%to about 5% of xylitol; (i) about 0.1% to about 2% of sucralose; (j)about 0.1% to about 1% of polysorbate 80; (k) about 5% to about 30% ofwater; (l) about 0.01% or about 0.1% of one or more activepharmaceutical ingredients; and (m) optionally, about 0.1% to about 1%of one or more excipients comprising opacifiers, colorings, orflavorings.

Another embodiment described herein comprises a pharmaceuticalcomposition comprising (a) about 12% 150 Bloom gelatin; (b) about 5% 100Bloom gelatin; (c) about 1% gelatin hydrolysate; (d) about 2%polyethylene oxide; (e) about 13% glycerol; (f) about 0.8% citric acid;(g) about 42% maltitol; (h) about 4% xylitol; (i) about 0.3% sucralose;(j) about 0.4% polysorbate 80; (k) about 20% water; and (l) about 0.025%or about 0.05% fluticasone propionate.

Another embodiment described herein comprises a pharmaceuticalcomposition comprising a second active ingredient, wherein the secondactive pharmaceutical ingredient comprises about 0.5% to about 5% byweight of lidocaine, prilocaine, or a combination thereof, and theweight percentage of maltitol is reduced accordingly.

Another embodiment described herein comprises a pharmaceuticalcomposition comprising any of the compositions described herein fortreating, retarding the progression of, prophylaxis of, delaying theonset of, ameliorating, or reducing the symptoms of one or more ofesophageal, oral, or buccal inflammation, eosinophilic esophagitis, orallichen planus, aphthous stomatitis, odynophagia, acid reflux, dysphagia,oral, esophageal or peptic ulcers, heart burn, chest pain, abdominalpain, nausea, vomiting, coughing, sore throat, decrease in appetite, orfailure to thrive.

Another embodiment described herein comprises a pharmaceuticalcomposition comprising any of the compositions described herein fortreating a subject suffering from one or more of oral or esophagealinflammation, eosinophilic esophagitis, inflammatory bowel diseaseinvolving the esophagus, oral lichen planus, aphthous stomatitis,Crohn's disease, esophageal inflammation secondary to caustic/irritantingestion, recurrent esophageal strictures of any cause and includingirritant ingestion, pill-induced esophagitis, systemic diseases,congential diseases, epidermolysis bullosa, trauma, or post-surgeryinflammation.

Another embodiment described herein comprises a method for treating,retarding the progression of, prophylaxis of, delaying the onset of,ameliorating, or reducing the symptoms of one or more of esophageal,oral, or buccal inflammation, eosinophilic esophagitis, oral lichenplanus, aphthous stomatitis, odynophagia, acid reflux, dysphagia, oral,esophageal or peptic ulcers, heart burn, chest pain, abdominal pain,nausea, vomiting, coughing, sore throat, decrease in appetite, orfailure to thrive, comprising administering to a subject in need thereofany of the pharmaceutical compositions described herein.

Another embodiment described herein comprises a method for treating asubject suffering from one or more of esophageal oral, or buccalinflammation, eosinophilic esophagitis, inflammatory bowel diseaseinvolving the esophagus, oral lichen planus, aphthous stomatitis,Crohn's disease, esophageal inflammation secondary to caustic/irritantingestion, recurrent esophageal strictures of any cause and includingirritant ingestion, pill-induced esophagitis, systemic diseases,congential diseases, epidermolysis bullosa, trauma, or post-surgeryinflammation comprising administering to the subject in need thereof anyof the pharmaceutical compositions described herein.

Another embodiment described herein comprises a means for treating asubject suffering from one or more of esophageal oral, or buccalinflammation, eosinophilic esophagitis, inflammatory bowel diseaseinvolving the esophagus, oral lichen planus, aphthous stomatitis,Crohn's disease, esophageal inflammation secondary to caustic/irritantingestion, recurrent esophageal strictures of any cause and includingirritant ingestion, pill-induced esophagitis, systemic diseases,congential diseases, epidermolysis bullosa, trauma, or post-surgeryinflammation comprising administering to the subject in need thereof anoral topical non-systemic pharmaceutical composition comprising any ofthe pharmaceutical compositions described herein.

A method for manufacturing an oral topical non-systemic pharmaceuticaldosage form suitable for chewing, sucking, or buccal dissolutioncomprising: (a) combining gelatin, glycerol, water, maltitol, xylitol,sucralose, citric acid, polysorbate 80 and one or more activepharmaceutical ingredient to produce a matrix fill solution; (b)combining one or more gelatins, glycerol, water, maltitol, xylitol,sucralose, and citric acid to produce a shell gel mass; (c) casting theshell gel mass into films using heat-controlled drums or surfaces; and(d) injecting the matrix fill solution between the shell ribbons, andforming a soft lozenge using rotary die encapsulation technology.

Another embodiment described herein comprises a soft lozenge produced bythe methods described herein. In one aspect, the soft lozenge comprisesany of the composition described herein.

Another embodiment described herein comprises a kit for dispensing anyof the oral pharmaceutical compositions described herein, comprising:(a) at least one oral pharmaceutical composition suitable for chewing,sucking, or buccal dissolution comprising one or more corticosteroids;(b) at least one receptacle comprising a tamper evident, moisture proofpackaging that reduces the ability of removing the oral, entericpharmaceutical composition comprising blister or strip packs, aluminumblister, transparent or opaque polymer blister with pouch, polypropylenetubes, colored blister materials, tubes, bottles, and bottles optionallycontaining a child-resistant feature, optionally comprising a desiccant,such as a molecular sieve or silica gel; and (c) optionally, an insertcomprising instructions or prescribing information for the oralpharmaceutical composition. In one aspect, the oral pharmaceuticalcomposition comprises any of the compositions described herein.

Another embodiment described herein comprises a pharmaceuticalcombination comprising a pharmaceutical composition described herein andone or more additional therapeutic compounds. In one aspect, the one ormore additional therapeutic compound comprises one or more of antacids(e.g., calcium hydroxide, magnesium hydroxide, alluminum hydroxide,sodium bicarbonate, calcium carbonate, bismuth subsalicylate, or others;Maalox, Mylanta, Gaviscon, Kaopectate, Pepto-Bismol) sucralfate,esomeprazole, omeprazole, lansoprazole, dexlansoprazole, esomeprazole,pantoprazole, rabeprazole, ilaprazole, cimetidine, ranitidine,famotidine, lafutidine, nizatidine, roxatidine, tiotidine, salmeterol,albuterol, aclidinium, ipratropium, tiotropium, umeclidinium,acrivastine, azelastine, bilastine, brompheniramine, buclizine,bromodiphenhydramine, carbinoxamine, chlorpromazine, cyclizine,chlorphenamine, chlorodiphenhydramine, clemastine, cyproheptadine,dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimetindene,diphenhydramine, doxylamine, ebastine, embramine, fexofenadine,hydroxyzine, loratadine, meclozine, mirtazapine, olopatadine,orphenadrine, phenindamine pheniramine, phenyltoloxamine, promethazine,quetiapine, rupatadine, tripelennamine, triprolidine, clobenpropit,ciproxifan, conessine, thioperamide, montelukast, zafirlukast,pranlukast, mepolizumab, reslizumab, omalizumab, infliximab,azathioprine, 6-mercaptopurine, thioguanine, aspirin (acetylsalicylicacid), ibuprofen, naproxen, ketoprofen, celecoxib, diclofenac, amikacin,gentamicin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin,streptomycin, spectinomycin, geldanamycin, herbimycin, rifaximin,loracarbef, ertapenem, doripenem, imipenem/cilastatin, meropenem,cefadroxil, cefazolin, cefalotin, cefalexin, cefaclor, cefamandole,cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren,cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten,ceftizoxime, ceftriaxone, cefepime, ceftaroline fosamil, ceftobiprole,teicoplanin, vancomycin, telavancin, dalbavancin, oritavancin,clindamycin, lincomycin, daptomycin, azithromycin, clarithromycin,dirithromycin, erythromycin, roxithromycin, troleandomycin,telithromycin, spiramycin, aztreonam, furazolidone, nitrofurantoin,linezolid, posizolid, radezolid, torezolid, amoxicillin, ampicillin,azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin,mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillinV, piperacillin, temocillin, ticarcillin, amoxicillin/clavulanate,ampicillin/sulbactam, piperacillin/tazobactam, ticarcillin/clavulanate,bacitracin, colistin, polymyxin B, ciprofloxacin, enoxacin,gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin,nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin,sparfloxacin, temafloxacin, mafenide, sulfacetamide, sulfadiazine,silver sulfadiazine, sulfadimethoxine, sulfamethizole, sulfamethoxazole,sulfanilimide, sulfasalazine, sulfisoxazole,trimethoprim-sulfamethoxazole, sulfamidochrysoidine, demeclocycline,doxycycline, minocycline, oxytetracycline, tetracycline, clofazimine,dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid,pyrazinamide, rifampicin, rifabutin, rifapentine, streptomycin,arsphenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole,mupirocin, platensimycin, quinupristin/dalfopristin, thiamphenicol,tigecycline, tinidazole, trimethoprim, or combinations thereof.

Another embodiment described herein comprises a method for treating,retarding the progression of, prophylaxis of, delaying the onset of,ameliorating, or reducing the symptoms of one or more of esophagealoral, or buccal inflammation, eosinophilic esophagitis, inflammatorybowel disease involving the esophagus, oral lichen planus, aphthousstomatitis, Crohn's disease, esophageal inflammation secondary tocaustic/irritant ingestion, recurrent esophageal strictures of any causeand including irritant ingestion, pill-induced esophagitis, systemicdiseases, congential diseases, epidermolysis bullosa, trauma, orpost-surgery inflammation comprising administering to a subject in needthereof any of the pharmaceutical combinations described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. (A) Linear scale plot of the mean plasma concentration over timefor the Test fluticasone propionate lozenge and the Referencefluticasone propionate aerosol. (B) Log scale plot of the same datashown in (A).

DETAILED DESCRIPTION

Described herein are topical, non-systemic, slow-release oralpharmaceutical compositions comprising chewable, suckable, dissolvablesoft lozenges or swallowable liquid formulations comprising one or moreactive pharmaceutical ingredients.

The oral pharmaceutical compositions described herein suitable forchewing, sucking, buccal dissolution, or swallowing comprising one ormore corticosteroids as at least one of the active pharmaceuticalingredients, and methods for preparation thereof. The oral compositionprovides topical, non-systemic administration and slow release of one ormore active pharmaceutical ingredients to the oral cavity and uppergastrointestinal track, including the esophagus. The soft lozengecomprises a firm, gelatinous solid or semi-solid matrix fillencapsulated by a gelatin capsule shell. Liquid formulations comprisesolutions, syrups, suspensions, elixirs or concentrates. The phrase“organoleptic properties” as used herein refers to the sensory aspectsexperienced by one or more subjects, including but not limited to,sight, smell, taste, mouth feel, moisture content/dryness, plasticity,chewability, dissolution, residue, and aftertaste.

The phrase “suitable for chewing, sucking, or buccal dissolution” asused herein refers to the propensity of the soft lozenges describedherein to dissolve in a subject's mouth by passive incubation in theoral cavity, or actively by sucking, chewing, or mastication to deliverone or more active pharmaceutical ingredients to the oral cavity andesophagus. In one aspect, the soft lozenge can dissolve passively overtime in the subject's saliva. In another aspect, the soft lozenge can besucked by the subject. In another aspect, the soft lozenge can be chewedby the subject. In another aspect, the soft lozenge may be ingested by acombination of dissolving, sucking, or chewing by the subject.Regardless of the mode of oral dissolution, the soft lozenge providestopical delivery of one or more active pharmaceutical ingredients to theoral cavity and esophagus.

The terms “active ingredient” or “active pharmaceutical ingredient” asused herein refer to a pharmaceutical agent, active ingredient,compound, or substance, compositions, or mixtures thereof, that providea pharmacological, often beneficial, effect. In one embodiment, theactive pharmaceutical ingredient is one or more corticosteroids.

The term “topical” as used herein refers to the administration of anactive pharmaceutical ingredient directly to a portion of a subject'sbody, particularly to the mucus membranes. In one embodiment describeherein, topical refers to the administration of one or morecorticosteroids or other active pharmaceutical ingredients to the innerlumen of the oral cavity and esophagus.

The term “contact” as used herein refers to the presence of thedissolved dosage form directly on the mucous membranes or tissues of theoral cavity or esophagus.

The term “non-systemic” as used herein refers to the administration ofan active pharmaceutical ingredient that is not sufficiently absorbed toa significant extent so that it is transported throughout the body viathe circulatory system or detectable in blood or plasma. In oneembodiment described herein, an active pharmaceutical ingredient istopically administered at a dosage insufficient to become systemicallycirculated.

The term “delayed release” as used herein refers to the release of theactive ingredient over a period of time that is subsequent to thedissolution of the dosage form.

The term “dissolution” as used herein refers to the completedisintegration of the dosage form either intra-orally or in-vitro.

The terms “dosage” or “dose” as used herein denote any forms of theactive ingredient formulation that contain an amount sufficient toproduce a therapeutic effect with a single administration. The dosageform described herein is for oral administration. The oral dosage formmay also be a liquid comprising a suspension, syrup, elixir orconcentrate, wherein the corticosteroid may be formulated as a viscousliquid suspension having enough viscosity such that upon drinking, thesuspension adheres to the esophageal surface. The oral dosage form mayalso be a soft lozenge.

The terms “active pharmaceutical ingredient load” or “drug load” as usedherein refer to the quantity (mass) of the active pharmaceuticalingredient comprised in a single liquid dosage or soft lozenge.

The term “formulation” or “composition” as used herein refers to thedrug in combination with pharmaceutically acceptable excipients. Thisterm includes orally administrable formulations as well as formulationsadministrable by other means.

As used herein, the term “pharmaceutical composition” refers to acomposition comprising at least on active ingredient, nutraceutical,nutritional, or vitamin.

The term “release modifier” as used herein refers to a substance thatslows the dissolution and release of the active ingredient from the softlozenge.

The term “pH modifier” as used herein refers to a substance that adjuststhe pH of a composition. In one embodiment described herein, pHmodifiers comprise one or more organic acids.

The term “absolute bioavailability” as used herein refers to thefraction of a drug or active pharmaceutical ingredient absorbed throughnon-intravenous administration (e.g., oral administration) as comparedto intravenous administration of the same drug or active pharmaceuticalingredient.

The term “C_(max)” as used herein refers to the maximum observed blood(plasma, serum, or whole blood) concentration or the maximum bloodconcentration calculated or estimated from a concentration to timecurve, and is expressed in units of mg/L or ng/mL, as applicable.

The term “C_(min)” as used herein refers to the minimum observed blood(plasma, serum, or whole blood) concentration or the minimum bloodconcentration calculated or estimated from a concentration to timecurve, and is expressed in units of mg/L or ng/mL, as applicable.

The term “C_(avg)” as used herein refers to the blood (plasma, serum, orwhole blood) concentration of the drug within the dosing interval, iscalculated as AUC/dosing interval, and is expressed in units of mg/L orng/mL, as applicable.

The term “T_(max)” as used herein refers to the time afteradministration at which C_(max) occurs, and is expressed in units ofhours (h) or minutes (min), as applicable.

The term “AUG_(0→τ)” as used herein refers to the area under the blood(plasma, serum, or whole blood) concentration versus time curve fromtime zero to time tau (τ) over a dosing interval at steady state, wheretau is the length of the dosing interval, and is expressed in units ofh·mg/L or h·ng/mL, as applicable. For example, the term AUC_(0→12) asused herein refers to the area under the concentration versus time curvefrom 0 to 12 hours.

The term “AUC_(0→∞)” as used herein refers to the area under the blood(plasma, serum, or whole blood) concentration versus time curve fromtime 0 hours to infinity, and is expressed in units of h·mg/L orh·ng/mL, as applicable.

The term “room temperature” as used herein refers to common ambienttemperatures found in pharmaceutical laboratories ranging from about 20°C. to about 27° C.

The term “titration” as used herein refers to the incremental increasein drug dosage to a level that provides the optimal therapeutic effect.

The term “treating” refers to administering a therapy in an amount,manner, or mode effective to improve a condition, symptom, or parameterassociated with a disorder.

The term “prophylaxis” refers to preventing or reducing the progressionof a disorder, either to a statistically significant degree or to adegree detectable to one skilled in the art.

The term “substantially” as used herein means to a great or significantextent, but not completely.

The term “about” as used herein refers to any values, including bothintegers and fractional components that are within a variation of up to±10% of the value modified by the term “about.”

As used herein, “a” or “an” means one or more unless otherwisespecified.

Terms such as “include,” “including,” “contain,” “containing,” “have,”“having,” and the like mean “comprising.”

The term “or” can be conjunctive or disjunctive.

One embodiment described herein, is a topical, non-systemic,slow-releasing oral pharmaceutical composition comprising a chewable,suckable, or dissolvable soft lozenge or liquid formulation comprisingone or more active pharmaceutical ingredients. In one embodimentdescribed herein, the pharmaceutical composition slowly dissolves in asubject's oral cavity and provides contact of the active pharmaceuticalingredient to the oral cavity and esophagus over a prolonged period. Inone aspect, the pharmaceutical composition can be chewed or masticated.In another aspect, the pharmaceutical composition can be sucked. Inanother aspect, the pharmaceutical composition can be swallowed,particularly when the composition is a liquid. In another aspect, thepharmaceutical composition can be allowed to slowly dissolve in the oralcavity. In another aspect, the pharmaceutical composition can bemasticated, sucked, and/or allowed to passively dissolve in the oralcavity at the subject's discretion. Regardless of the mode of oraldissolution, the compositions described herein provide slow releasingand prolonged topical contact of the active pharmaceutical to the oralcavity and esophagus.

In one embodiment described herein, the pharmaceutical compositioncomprises one or more corticosteroids that are slowly released in theoral cavity and provide topical, non-systemic treatment of the oralcavity and esophagus. The dosage form of corticosteroid is topicallyadministered to the oral cavity and esophagus, but the dosage quantityof corticosteroid is insufficient to be systemically circulated. In oneaspect, the dosage form coats the esophagus. In one aspect, the oralpharmaceutical composition described herein is for the topical treatmentof esophagitis or eosinophilic esophagitis (EoE).

In one embodiment described herein, the oral pharmaceutical compositioncomprises a chewable, suckable, or dissolvable soft lozenge. In anotherembodiment, the soft lozenge comprises a gelatinous solid or semi-solidfill or matrix composition that is encapsulated within a soft shellcomposition. In one embodiment, the pharmaceutical composition comprisesa fill composition as shown in Tables 1-2 and a shell composition asshown in Tables 3-4. In another embodiment, the pharmaceuticalcomposition comprises the formulation shown in Table 5.

One embodiment described herein, is an oral pharmaceutical compositioncomprising a gel mass suitable for forming a soft lozenge fill or matrixcomposition. In one embodiment, the soft lozenge fill or matrixcomposition comprises the composition shown in Table 1.

TABLE 1 Exemplary Soft Lozenge Matrix Fill Composition ExemplaryIngredients Weight Percentage (%) Film-forming Polymer(s) 5-30 ReleaseModifier(s) 0.5-10  Plasticizer(s) 5-20 pH Modifier(s) 0.5-5  Sweetener(s) 10-80  Solubilizing Agent(s) 0.1-5   Solvent(s) 5-30 ActivePharmaceutical Ingredients (API) 0.001-1    Second API 1-10 Excipients,optional 0-10 TOTAL 100%

Another embodiment described herein is an oral soft lozenge fillcomposition comprising one or more film-forming polymers, one or moreplasticizers, one or more pH modifiers, one or more solubilizing agents,one or more release modifiers, one or more solvents, one or moresweeteners, and one or more active pharmaceutical ingredients. Inanother embodiment the soft lozenge fill composition comprises one ormore excipients, including but not limited to coloring agents,flavorings, or the like.

In one embodiment described herein, the soft lozenge fill compositioncomprises that shown in Table 2.

TABLE 2 Exemplary Soft Lozenge Matrix Fill Composition Weight FunctionalComponent Exemplary Components Percentage (%) Film-forming PolymersGelatin, 80-180 Bloom 5-20 Gelatin Hydrolysate 0-10 Release Modifier(s)Polyethylene oxide, 6 × 10⁵- 0.5-10  7 × 10⁶ MW Plasticizer(s) Glycerol5-20 pH Modifier(s) Citrate, Lactate, Fumarate 0.1-5   Sweetener(s)Maltitol, Mannitol 10-70  Xylitol 0-10 Sucralose 0.1-5   SolubilizingAgent(s) Polysorbate 80 0.1-2   Solvent Water 5-30 Active Pharmaceuticalfluticasone, budesonide, 0.001-0.5   Ingredients (API) prednisone, othercorticosteroids Second API Lidocaine, Prilocaine, 1-10 Excipients,optional flavorings, colorings, etc 0-10 TOTAL 100%

Another embodiment described herein is an oral soft lozenge shellcomposition. The shell composition is used to enrobe or encapsulate thesoft lozenge fill or matrix compositions described herein. In oneembodiment, the soft lozenge shell composition comprises that shown inTable 3.

TABLE 3 Exemplary Soft Lozenge Shell Composition Exemplary IngredientsWeight Percentage (%) Film-forming Polymer(s) 10-50  Plasticizer(s) 5-20pH Modifier(s) 0.1-5   Sweetener(s) 10-80  Solvent(s) 5-30 Excipients,optional 0-10 TOTAL 100%

Another embodiment described herein is a composition for a soft lozengeshell composition comprising one or more film-forming polymers, one ormore plasticizers, one or more pH modifiers, one or more solvents, andone or more sweeteners. In another embodiment the soft lozenge shellcomposition comprises one or more excipients, including but not limitedto coloring agents, flavorings, opacifiers, or the like.

In one embodiment described herein, the soft lozenge shell compositioncomprises that shown in Table 4.

TABLE 4 Exemplary Soft Lozenge Shell Composition Weight FunctionalComponent Exemplary Components Percentage (%) Film-forming Gelatin, 150Bloom (or other 5-30 Polymers high Bloom) Gelatin, 100 Bloom (or other0-20 low Bloom) Gelatin Hydrolysate 0-10 Partially Hydrolyzed Gelatin0-10 Plasticizer(s) Glycerol 5-30 pH Modifier(s) Citrate, Lactate orFumarate 0.1-5   Sweetener(s) Mannitol, Maltitol 5-30 Sucralose 0.1-2  Xylitol 1-10 Solvent Water 5-30 Excipients, flavorings, colorings,opacifiers, 0-10 optional etc TOTAL 100%

Another embodiment described herein is an oral soft lozenge composition.The soft lozenge composition comprises a shell as described herein thatenrobes or encapsulates a soft lozenge fill or matrix composition asdescribed herein. In one embodiment, the soft lozenge compositioncomprises that shown in Table 5.

TABLE 5 Exemplary Soft Lozenge Total Composition (Shell and Fill)Exemplary Ingredients Weight Percentage (%) Film-forming Polymer(s)10-40  Release Modifier(s) 0.5-10   Plasticizer(s) 5-30 pH Modifier(s)0.5-5   Sweetener(s) 10-70  Solubilizing Agent(s) 0.1-1   Solvent(s)5-30 Active Pharmaceutical Ingredients 0.005-0.5    (API, e.g.,corticosteroids) Second API (topical anesthetic, e.g., lidocaine) 1-10Excipients 0-10 TOTAL 100%

In one embodiment described herein, the soft lozenge compositioncomprises that shown in Table 6.

TABLE 6 Exemplary Soft Lozenge Total Composition (Shell and Fill) WeightPercentage Component Exemplary Components (%) Film-forming Gelatin, 150Bloom 1-20 Polymers Gelatin, 100 Bloom 1-20 Gelatin Hydrolysate 0-10Partially Hydrolyzed Gelatin 0-10 Release Polyethylene oxides, 6 × 10⁵−7× 0.5-10   Modifier(s) 10⁶ MW Plasticizer(s) Glycerol 1-20 pHModifier(s) Citric Acid, Anhydrous 0.1-5   Sweetener(s) Maltitol (75%solution; e.g., Lycasin ® 10-60  80/55) Xylitol 0.5-5   Sucralose0.01-5    Solubilizing Polysorbate 80 0.01-5    Agent(s) Solvent Water5-40 Active Fluticasone propionate 0.005-0.5    PharmaceuticalIngredient Second API Lidocaine, Prilocaine, combination 1-10 thereofExcipients Titanium dioxide, FD&C colorings, 0-10 flavors TOTAL 100%

In one embodiment described herein, the soft lozenge compositioncomprises a shell composition and a fill composition that have similarcompositions. In one embodiment, the soft lozenge fill compositioncomprises similar components as the soft lozenge shell compositionexcept that the fill composition comprises one or more solubilizingagents and one or more release modifiers and the shell composition canoptionally comprise one or more opacifiers, colors, or flavors. In oneembodiment described herein, the matrix fill composition is firmer andslower to dissolve in the oral cavity compared with the shellcomposition.

In one embodiment described herein, the pharmaceutical compositionscomprise liquid dosage forms. In one aspect the liquid dosage formcomprises a suspension. In another aspect, the liquid dosage formcomprises syrup. In another aspect the liquid dosage form comprises aconcentrate.

Another embodiment described herein is a composition for a liquid dosageform comprising one or more release modifiers, one or more film formingpolymers, one or more plasticizers, one or more, pH modifiers, one ormore sweeteners, one or more solubilizing agents, one or more solvents.In another embodiment, the liquid dosage form comprises one or moreexcipients, including but not limited to coloring agents, flavorings,opacifiers, thickeners or the like.

In one embodiment described herein, the pharmaceutical compositionsdescribed herein comprise one or more film-forming polymers. Film-formerpolymers that are useful for the pharmaceutical compositions describedherein are gelatin, partially hydrolyzed gelatin, collagen, partiallyhydrolyzed collagen; sodium or calcium alginate; natural and modifiedstarch, starch hydrolysates, pectins or amylopectins;hydroxypropylmethylcellulose (HPMC), methylcellulose, cellulose;carrageenan (e.g., iota carrageenan and kappa carrageenan), orcombinations thereof. In one embodiment described herein, thepharmaceutical compositions comprise one or more film-forming polymerscomprising one or more gelatins or gelatin hydrolysates.

Examples of gelatin compositions that are useful for the pharmaceuticalcompositions described herein comprise acid bone gelatin, pig skingelatin, chicken skin gelatin, fish gelatin, acid hide gelatin, gelatinhydrolysate, lime bone gelatin, or combinations thereof. Gelatins areoften classified as either “Type A” or “Type B” gelatin. Type A gelatinis derived from the acid hydrolysis of collagen (e.g., acid bone gelatinor pig skin gelatin), while Type B gelatin (e.g., lime bone gelatin) isderived from the alkaline hydrolysis of collagen. Traditionally, bovinebones and skins are used as raw materials for manufacturing Type A andType B gelatin, while porcine skins are used extensively formanufacturing Type A gelatin. In addition, at neutral pH values, Type Agelatins (e.g., acid-processed gelatins) are typically net cationic(e.g., isoelectric point of about 7-9) and Type B gelatins (e.g.,alkali-processed gelatins) are typically net anionic (e.g., isoelectricpoint of about 4.5-5.3). Type A gelatin typically has higher plasticityand elasticity than type B gelatin; type B gelatin typically has highergel strength than type A gelatin.

The strength of gelatins is typically defined by “Bloom strength” orgrade. The Bloom test determines the weight (in grams) needed by a0.5-inch diameter probe to deflect the surface of a gel 4-mm withoutbreaking it. The result is expressed as “Bloom” or “Bloom strength.” Thepharmaceutical compositions described herein utilize gelatins with Bloomstrengths in the range of about 20 Bloom to about 400 Bloom, includingeach integer within the specified range. In one embodiment, Bloomstrengths for the pharmaceutical compositions described herein are about50 Bloom to about 250 Bloom including each integer within the specifiedrange. In some embodiments, the gelatin Bloom strength is about 50Bloom, about 80 Bloom, about 100 Bloom, about 120 Bloom, about 150Bloom, about 180 Bloom, about 200 Bloom, or about 250 Bloom. In oneembodiment, the gelatin Bloom strength is about 100 Bloom. In anotherembodiment, the gelatin Bloom strength is about 150 Bloom. In anotherembodiment, the gelatin Bloom strength is 195 Bloom. In anotherembodiment, the gelatin Bloom strength is 200 Bloom. In another aspect,the film-forming polymers comprise one or more of gelatin with variousBloom strengths, partially hydrolyzed gelatin, hydrolyzed gelatin, orcombinations thereof.

In another embodiment described herein, the pharmaceutical compositionsdescribed herein comprises one or more plasticizers. As used herein, aplasticizer is a substance, often a polyol that provides flexibility andsoftens the lozenge. In one embodiment, the plasticizer comprises one ormore of glycerol, sorbitol, partially dehydrated sorbitol (a blend ofD-sorbitol, 1,4-sorbitan, mannitol, and water; e.g., Sorbitol Special®(SPI Pharma); Anidrisorb® or Polysorb®, (Roquette), corn syrup, xylitol,mannitol, propylene glycol, low molecular weight polyethylene glycols,poly-alcohols with 3 to 6 carbon atoms, or combinations thereof. In oneembodiment, the plasticizer comprises glycerol, sorbitol, orcombinations thereof.

In another embodiment described herein, the pharmaceutical compositionsdescribed herein comprise one or more sweeteners. In one embodiment, thesweetener comprises one or more of maltitol (e.g., hydrogenated starchhydrolysates; e.g., Lycasin® 80/55, Roquette), xylitol (Xylisorb 300®),sucralose, aspartame, steviol glycosides (e.g., Stevia®, Truvia®),thaumatin (e.g., Talin®), glycyrrhizic acid salts (MagnaSweet®),mannitol, or combinations thereof. In one aspect, the sweetenercomprises sucralose, sucrose, xylitol, or combinations thereof.

In another embodiment described herein, the pharmaceutical compositioncomprises one or more pH modifiers. In one embodiment, the pH modifiercomprises one or more organic acids. In another embodiment, the pHmodifier comprises one or more of citric acid, acetic acid, lactic acid,malic acid, tartaric acid, glutamic acid, aspartic acid, malic acid,succinic acid, fumaric acid, or combinations thereof. In one aspect, thepH modifier comprises citric acid, lactic acid, or fumaric acid. In oneaspect, the pH modifier comprises citric acid.

In another embodiment described herein, the pharmaceutical compositioncomprises one or more solubilizing agents. In one embodiment, thesolubilizing agent comprises one or more of polysorbate 20, polysorbate40, polysorbate 60, polysorbate 80, diethanolamine, glycerylmonostearate, lanolin alcohols, lecithin, mono- and di-glycerides,monoethanolamines, oleic acids, oleyl alcohols, poloxamer,polyoxyethylene 50 stearate, polyoxyl 35 castor oil, polyoxyl 40hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyl 20cetostearyl ether, polyoxyl 40 stearate, propylene glycol diacetate,propylene glycol monostearate, sodium lauryl sulfate, sodium stearate,sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate,sorbitan monostearate, stearic acid, trolamine, emulsifying wax, orcombinations thereof. In one aspect, the solubilizing agent comprisespolysorbate 80.

In another embodiment described herein, the pharmaceutical compositioncomprises one or more release modifiers. Suitable release modifierscomprise one or more of polyethylene oxides, methylcellulose,hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethylcellulose, hydroxymethyl cellulose, polymethylmethacrylate,polyhydroxyethylmethacrylate, polyvinylpyrrolidone, copovidone,polyvinyl alcohol, copolymers of polyvinylpyrrolidone and polyvinylacetate, or combinations thereof. For example, Methocel™ K100M,Methocel™ A4M, Premium LV CR, K4M Premium CR, K 15M Premium CR, K100Premium CR, E4M Premium CR, E10M Premium CR, or E4M Premium (DowChemical Co.), CELLOSIZE™, or WALOCEL™ CRT may be used as releasemodifiers in the compositions described herein. In one embodimentdescribed herein, the release modifier comprises one or morepolyethylene oxides.

In one embodiment described herein, the release modifier comprises apolyethylene oxide. As described herein, polyethylene oxide polymershave an approximate molecular weight (M_(v)) of at least about 600,000to about 10,000,000 or greater. In one aspect, the release modifier maycomprise a high molecular weight polyethylene oxide having a molecularweight (M_(v)) of about 600,000 to about 10,000,000, including eachinteger within the specified range. In another aspect, the releasemodifier may comprise a high molecular weight polyethylene oxide havinga molecular weight (M_(v)) of about 4,000,000 to about 10,000,000,including each integer within the specified range. In another aspect,the release modifier may comprise a high molecular weight polyethyleneoxide having a molecular weight (M_(v)) of about 4,000,000 to about8,000,000, including each integer within the specified range. In anotheraspect, the release modifier may comprise a polyethylene oxide having amolecular weight (M_(v)) of about 600,000, about 700,000, about 800,000,about 900,000, about 1,000,000, about 2,000,000, about 3,000,000, about4,000,000, about 5,000,000, about 6,000,000, about 7,000,000, about8,000,000, about 9,000,000 or about 10,000,000. In another aspect, therelease modifier may comprise a high molecular weight polyethylene oxidehaving a molecular weight (M_(v)) of about 4,000,000. In another aspect,the release modifier may comprise a high molecular weight polyethyleneoxide having a molecular weight (M_(v)) of about 5,000,000. In anotheraspect, the release modifier may comprise a high molecular weightpolyethylene oxide having a molecular weight (M_(v)) of about 7,000,000.

The molecular weight measurements of polyethylene oxide may beapproximated using rheological measurements using a viscometer (e.g.,weight average molecular weight, M_(v)). For example, polyethylene oxideis considered to have an approximate molecular weight (M_(v)) of 600,000when a 5% (by wt) aqueous solution of polyethylene oxide using aBrookfield viscometer Model RVF, spindle No. 2, at 2 rpm, at 25° C.shows a viscosity range of 30 to 50 mPa s (cP). Polyethylene oxide isconsidered to have an approximate molecular weight (M_(v)) of 1,000,000when a 2% (by wt) aqueous solution of polyethylene oxide using aBrookfield viscometer Model RVF, spindle No. 1, at 10 rpm, at 25° C.shows a viscosity range of 400 to 800 mPa s (cP). Polyethylene oxide isconsidered to have an approximate molecular weight (M_(v)) of 2,000,000when a 2% (by wt) aqueous solution of polyethylene oxide using aBrookfield viscometer Model RVF, spindle No. 3, at 10 rpm, at 25° C.shows a viscosity range of 2000 to 4000 mPa s (cP). Polyethylene oxideis considered to have an approximate molecular weight (M_(v)) of4,000,000 when a 1% (by wt) aqueous solution of polyethylene oxide usinga Brookfield viscometer Model RVF, spindle No. 2, at 2 rpm, at 25° C.shows a viscosity range of 1650 to 5500 mPa s (cP). Polyethylene oxideis considered to have an approximate molecular weight (M_(v)) of4,000,000 when a 2% (by wt) aqueous solution of polyethylene oxide usinga Brookfield viscometer Model RVF, spindle No. 2, at 2 rpm, at 25° C.shows a viscosity range of 3300 to 11000 mPa s (cP). Polyethylene oxideis considered to have an approximate molecular weight (M_(v)) of5,000,000 when a 1% (by wt) aqueous solution of polyethylene oxide usinga Brookfield viscometer Model RVF, spindle No. 2, at 2 rpm, at 25° C.shows a viscosity range of 5500 to 7500 mPa s (cP). Polyethylene oxideis considered to have an approximate molecular weight (M_(v)) of5,000,000 when a 1.5% (by wt) aqueous solution of polyethylene oxideusing a Brookfield viscometer Model RVF, spindle No. 2, at 2 rpm, at 25°C. shows a viscosity range of 8250 to 11250 mPa s (cP). Polyethyleneoxide is considered to have an approximate molecular weight (M_(v)) of7,000,000 when a 1% (by wt) aqueous solution of polyethylene oxide usinga Brookfield viscometer Model RVF, spindle No. 2, at 2 rpm, at 25° C.shows a viscosity range of 7500 to 10,000 mPa s (cP). Polyethylene oxideis considered to have an approximate molecular weight (M_(v)) of8,000,000 when a 1% (by wt) aqueous solution of polyethylene oxide usinga Brookfield viscometer Model RVF, spindle No. 2, at 2 rpm, at 25° C.shows a viscosity range of 10,000 to 15,000 mPa s (cP). Suitablepolyethylene oxide polymers with the above described viscosity andmolecular weight (M_(v)) values that are useful for the matricesdescribed are, for example, POLYOX™ polymers, such as WSR-205, WSR-1105,WSR N-12K, WSR N-60K, WSR-301, WSR Coagulant, WSR-303, WSR 308, UCARFLOCPolymers 300, 302, 304, and 309 commercially available from Dow. In oneembodiment described herein, the release modifier comprises thepolyethylene oxide polymer Polyox™ WSR-303 that has an approximatemolecular weight (viscosity average, M_(v)) of 7,000,000 and a 1%solution of the polymer has a viscosity of 7,500-10,000 cP at 25° C.using a Brookfield Model RVF viscometer, spindle No. 2, at 2 rpm.

The one or more release modifiers may comprise a viscosity of about 50cP to about 100,000 cP, including each integer within the specifiedrange. For example, the release modifiers comprise a viscosity of about50 cP, about 100 cP, about 200 cP, about 300 cP, about 400 cP, about 500cP, about 750 cP, about 1,000 cP, about 1,500 cP, about 2,000 cP, about2,500 cP, about 3,000 cP, about 3,500 cP, about 4,000 cP, about 4,500cP, about 5,000 cP, about 6,000 cP, about 7,000 cP, about 8,000 cP,about 9,000 cP, or about 10,000 cP, about 15,000 cP, about 20,000 cP,about 30,000 cP, about 40,000 cP, about 50,000 cP, about 60,000 cP,about 70,000 cP, about 80,000 cP, about 90,000 cP, about 100,000 cP,greater than 100,000 cP, or even greater.

In one embodiment described herein, the one or more release modifiersprovide slow release of the active pharmaceutical ingredient byretarding the dissolution of the dosage form.

In another embodiment described herein, in addition to the releasemodifiers, thickening agents may be used to control the release of theactive pharmaceutical ingredient and may comprise one or more ofpolyacrylic acid, methyl cellulose, alginic acid, chitosan,carboxymethyl cellulose, sodium carboxymethyl cellulose, locust beangum, xanthum gum, high swelling crosslinked polymers, or combinationsthereof.

In another embodiment described herein, the pharmaceutical compositionsdescribed herein comprises one or more solvents. In one aspect, thesolvent comprises water.

In another embodiment described herein, the pharmaceutical compositionsdescribed herein comprises one or more active pharmaceuticalingredients. In one embodiment the active pharmaceutical ingredientcomprises one or more corticosteroids. In another embodiment, the activepharmaceutical ingredient comprises one or more corticosteroids and oneor more topical anesthetics. In one embodiment, the activepharmaceutical composition comprises fluticasone propionate, lidocaine,prilocaine, or combinations thereof.

In one embodiment described herein, one or more film-forming polymerscomprise about 5% to about 70% by weight of the composition, includingeach integer within the specified range. In another embodiment, one ormore film-forming polymers comprise about 5% to about 30% by weight ofthe composition, including each integer within the specified range. Inanother embodiment, one or more film-forming polymers comprise about 10%to about 60% by weight of the composition, including each integer withinthe specified range. In another embodiment, one or more film-formingpolymers comprise about 10% to about 40% by weight of the composition,including each integer within the specified range. In one aspect, one ormore film-forming polymers comprise about 5% to about 20%; about 1% toabout 10%; about 5% to about 15%; about 1% to about 5%; about 10% toabout 20%; about 15% to about 20%; about 10% to about 15%, or about 1%to about 5% by weight of the composition, including each integer withinthe specified ranges.

In another embodiment described herein, one or more film-formingpolymers comprise about 0.5%, about 1%, about 2%, about 2.5%, about 3%,about 4%, about 5%, about 6%, about 7.5%, about 8%, about 9%, about 10%,about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about17%, about 18%, about 19%, about 20%, or about 25% by weight of thecomposition.

In one embodiment described herein, one or more plasticizers compriseabout 5% to about 30% by weight of the composition, including eachinteger within the specified range. In another embodiment, one or moreplasticizers comprise about 5% to about 20% by weight of thecomposition, including each integer within the specified range. Inanother embodiment, one or more plasticizers comprise about 10% to about30% by weight of the composition, including each integer within thespecified range. In another embodiment, one or more plasticizerscomprise about 5% to about 10% by weight of the composition, includingeach integer within the specified range. In another embodiment, one ormore plasticizers comprise about 10% to about 20% by weight of thecomposition, including each integer within the specified range. In oneaspect, one or more plasticizers comprise about 5% to about 20%; about1% to about 10%; about 5% to about 15%; about 1% to about 5%; about 10%to about 20%; about 15% to about 20%; about 10% to about 15%, or about1% to about 5% by weight of the composition, including each integerwithin the specified ranges.

In another embodiment described herein, one or more plasticizerscomprise about 5%, about 6%, about 7.5%, about 8%, about 9%, about 10%,about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%,about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, orabout 30% by weight of the composition.

In one embodiment, one or more pH modifiers comprise about 0.1% to about5% by weight of the composition, including each integer within thespecified range. In another embodiment, one or more pH modifierscomprise about 0.1% to about 1% by weight of the composition, includingeach integer within the specified range. In another embodiment, one ormore pH modifiers comprise about 0.5% to about 1% by weight of thecomposition, including each integer within the specified range. Inanother embodiment, one or more pH modifiers comprise about 0.1% toabout 0.5% by weight of the composition, including each integer withinthe specified range. In one aspect, one or more pH modifiers compriseabout 0.1% to about 0.5%; about 0.5% to about 1%; about 0.25% to about0.75%; about 0.75% to about 1%; about 1% to about 2%; about 0.5% toabout 1.5%; about 0.5% to about 0.75%, or about 0.25% to about 0.5% byweight of the composition, including each integer within the specifiedranges.

In another embodiment described herein, one or more pH modifierscomprise about 0.1%, about 0.2%, about 0.35, about 0.4%, about 0.5%,about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.2%,about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%,about 1.9%, about 2%, about 2.5%, about 3%, about 4%, or about 5% byweight of the composition.

In one embodiment, one or more release modifiers comprise about 0.5% toabout 10% by weight of the composition, including each integer withinthe specified range. In another embodiment, one or more releasemodifiers comprise about 1% to about 5% by weight of the composition,including each integer within the specified range. In anotherembodiment, one or more release modifiers comprise about 2% to about 5%by weight of the composition, including each integer within thespecified range. In one aspect, one or more release modifiers compriseabout 0.5% to about 2%; about 1% to about 3%; about 2% to about 4%;about 2.5% to about 5%; about 0.5% to about 1%, about 1% to about 2%;about 2% to about 3%; about 3% to about 4%; or about 4% to about 5% byweight of the composition, including each integer within the specifiedranges.

In another embodiment described herein, one or more release modifierscomprise about 0.2%, about 0.5%, about 1%, about 2%, about 3%, about 4%,about 5%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%,about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.2%, about 2.4%,about 2.6%, about 2.8%, about 2.9% about 3.1%, about 3.2%, about 3.4%,about 3.6%, about 3.8%, about 4.1%, about 4.2%, about 4.4%, about 4.6%,about 4.8%, about 5.5%, about 6%, about 7%, about 8%, about 9%, or about10% by weight of the composition.

In one embodiment described herein, one or more sweeteners compriseabout 10% to about 80% by weight of the composition, including eachinteger within the specified range. In another embodiment describedherein, one or more sweeteners comprise about 30% to about 70% by weightof the composition, including each integer within the specified range.In another embodiment described herein, one or more sweeteners compriseabout 15% to about 30% by weight of the composition, including eachinteger within the specified range. In another embodiment describedherein, one or more sweeteners comprise about 20% to about 60% by weightof the composition, including each integer within the specified range.In one aspect, one or more release modifiers comprise about 0.1% toabout 0.2%; about 0.1% to about 0.3%; about 0.1% to about 2%; about 1%to about 2.5%; about 1% to about 5%; about 2.5% to about 5%; about 1% toabout 10%; about 10% to about 15%, about 15% to about 20%; about 20% toabout 30%, about 30% to about 40%; about 40% to about 45%; about 45% toabout 50%; about 40% to about 50%; about 50% to about 60%; about 55% toabout 60%; about 60% to about 65%; about 60% to about 70%; or about 70%to about 80% by weight of the composition, including each integer withinthe specified ranges.

In another embodiment described herein, one or more sweeteners compriseabout 0.1%; about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 1%,about 2%, about 3%; about 4%, about 5%, about 6%, about 7%, about 8%,about 9%, about 10%, about 11%, about 12%, about 13%; about 14%, about15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%,about 30%, about 35%, about 40%, about 42%, about 45%, about 50%, about55%, about 58%, about 60%, about 62%, about 65%, or about 70% by weightof the composition.

In one embodiment described herein, one or more solubilizing agentscomprise about 0.1% to about 1% by weight of the composition, includingeach integer within the specified range. In another embodiment describedherein, one or more solubilizing agents comprise 0.1% to about 0.5% byweight of the composition, including each integer within the specifiedrange. In another embodiment described herein, one or more solubilizingagents comprise 0.1% to about 0.25% by weight of the composition,including each integer within the specified range. In one aspect, one ormore solubilizing agents comprise about 0.1% to about 0.5%; about 0.5%to about 0.75%; about 0.25% to about 0.5%; about 0.2% to about 0.7%;about 0.5% to about 1%; about 0.75% to about 1%; about 0.4% to about0.7%; about 0.3% to about 0.6%; about 0.4% to about 0.8%; about 0.25% toabout 0.75%; about 0.3% to about 0.9%; or about 0.75% to about 1% byweight of the composition, including each integer within the specifiedranges.

In another embodiment described herein, one or more solubilizing agentscomprise about 0.1%, about 0.2, about 0.3, about 0.35, about 0.4%, about0.45%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, orabout 1%, by weight of the composition.

In one embodiment described herein, one or more solvents comprise about5% to about 30% by weight of the composition, including each integerwithin the specified range. In another embodiment described herein, oneor more one or more solvents comprise about 10% to about 20% by weightof the composition, including each integer within the specified range.In another embodiment described herein, one or more one or more solventscomprise about 20% to about 30% by weight of the composition, includingeach integer within the specified range. In another embodiment describedherein, one or more one or more solvents comprise about 20% to about 25%by weight of the composition, including each integer within thespecified range. In one aspect, one or more solvents comprise about 5%to about 20%; about 10% to about 15%; about 10% to about 20%; about 15%to about 20%; about 15% to about 25%; about 15% to about 30%; about 20%to about 25%; about 20% to about 30%; or about 25% to about 30% byweight of the composition, including each integer within the specifiedranges.

In another embodiment described herein, one or more solvents compriseabout 5%, about 7.5%, about 10%, about 11%, about 12%, about 13%, about14%, about 15%, about 16%, about 17%. about 18%, about 19%, about 20%,about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about27%, about 28%, about 29%, or about 30% by weight of the composition.

In one embodiment described herein, one or more active pharmaceuticalingredients comprise about 0.005% to about 5% by weight of thecomposition, including each integer within the specified range. Inanother embodiment described herein, one or more active pharmaceuticalingredients comprise about 0.025% to about 0.05% by weight of thecomposition, including each integer within the specified range. Inanother embodiment described herein, one or more active pharmaceuticalingredients comprise about 0.015% to about 0.035% by weight of thecomposition, including each integer within the specified range. In oneaspect described herein, one or more active pharmaceutical ingredientscomprise about 0.005% to about 0.01%; about 0.01% to about 0.05%; about0.01% to about 0.025%; about 0.025% to about 0.1%; about 0.05% to about0.1%; about 0.016% to about 0.032%; about 0.02% to about 0.04%; about0.02% to about 0.05%; about 0.01% to about 0.04%; or about 0.02% toabout 0.04% by weight of the composition, including each integer withinthe specified ranges.

In another embodiment described herein, one or more activepharmaceutical ingredients comprise about 0.01%, about 0.016%, about0.02%, about 0.025%, about 0.03%, about 0.032%, about 0.04%, about0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%,about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%,about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, or about5% by weight of the composition.

In another embodiment described herein, one or more second activepharmaceutical ingredients comprise about 0.1%, about 0.2%, about 0.3%,about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%,about 1%, about 2%, about 3%, about 4%, or about 5% by weight of thecomposition.

In one embodiment described herein, one or more pharmaceuticallyacceptable excipients comprise about 0.0001% to about 10% by weight ofthe composition, including each integer within the specified range. Inanother embodiment described herein, one or more pharmaceuticallyacceptable excipients comprise about 0.1% to about 2% by weight of thecomposition, including each integer within the specified range. Inanother embodiment described herein, one or more pharmaceuticallyacceptable excipients comprise about 0.1% to about 1% by weight of thecomposition, including each integer within the specified range. In oneaspect, one or more pharmaceutically acceptable excipients compriseabout 0.1% to about 0.4%; 0.1% to about 0.5%; about 0.5% to about 1%;about 1% to about 1.5%, about 0.4% to about 1.2%; about 2% to about 5%;or about 5% to about 10% by weight of the composition, including eachinteger within the specified ranges.

In another embodiment described herein, one or more pharmaceuticallyacceptable excipients comprise about 0.0006%, about 0.0017%, about 0.1%,about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%,about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%,about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 2%,about 3%, about 4%, or about 5% by weight of the composition.

In another embodiment described herein, the one or more film-formingpolymers comprise gelatin having a Bloom of about 100 to about 150 and aweight percentage of about 5% to about 30% by weight of the composition,including each integer within the specified range. In one embodiment,gelatin having a Bloom of about 50 to 150 comprises about 5% to about10%; about 10% to about 15%; 10% to about 20%; about 15% to about 20%;about 20% to about 25%; or about 25% to about 30% by weight of thecomposition, including each integer within the specified ranges. In oneaspect, gelatin having a Bloom of about 50 to 150 comprises about 5%,about 7.5%, about 8%, about 9%, about 10%, about 11%, about 12%, about13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%,about 20%, about 25%, or about 30% by weight of the composition.

In another embodiment described herein, the one or more film-formingpolymers comprise a gelatin having a Bloom of about 50 to about 100 anda weight percentage of about 1% to about 20% by weight of thecomposition, including each integer within the specified range. Inanother embodiment, gelatin having a Bloom of about 50 to about 100comprises about 1% to about 5%; about 2.5% to about 5%; about 5% toabout 10%; about 10% to about 15%; about 2.5% to about 10%; or about4.7% to about 13% by weight of the composition, including each integerwithin the specified ranges. In one aspect, gelatin having a Bloom ofabout 100 comprises about 1%, about 2%, about 2.5%, about 3%, about 4%,about 4.7%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%,about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about17%, about 18%, about 19%, or about 20% by weight of the composition.

In another embodiment described herein, the one or more film-formingpolymers comprise gelatin hydrolysate at a weight percentage of about0.5% to about 5% by weight of the composition, including each integerwithin the specified range. In one embodiment, gelatin hydrolysatecomprises about 0.5% to about 1%; about 1% to about 2.5%; or about 0.5%to about 2.5% by weight of the composition, including each integerwithin the specified ranges. In one aspect, gelatin hydrolysatecomprises about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 0.9%,about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 4%, or about5%, by weight of the composition.

In another embodiment described herein, the one or more film-formingpolymers comprise partially hydrolyzed gelatin at a weight percentage ofabout 0.5% to about 5% by weight of the composition, including eachinteger within the specified range. In one embodiment, the partiallyhydrolyzed gelatin comprises about 0.5% to about 1%; about 1% to about2.5%; or about 0.5% to about 2.5% by weight of the composition,including each integer within the specified ranges. In one aspect,partially hydrolyzed gelatin comprises about 0%, 0.1%, about 0.25%,about 0.5%, about 0.75%, about 0.9%, about 1%, about 1.5%, about 2%,about 2.5%, about 3%, about 4%, or about 5%, by weight of thecomposition.

In another embodiment described herein, one or more plasticizerscomprise glycerol at a weight percentage of about 5% to about 30% byweight of the composition, including each integer within the specifiedrange. In one embodiment, glycerol comprises about 5% to about 20%;about 1% to about 10%; about 5% to about 15%; about 1% to about 5%;about 10% to about 20%; about 15% to about 20%; about 10% to about 15%;or about 1% to about 5% by weight of the composition, including eachinteger within the specified ranges. In one aspect, glycerol comprisesabout 5%, about 6%, about 7.5%, about 8%, about 9%, about 10%, about11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%,about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about24%, about 25%, about 26%, about 2′7%, about 28%, about 29%, or about30% by weight of the composition.

In another embodiment described herein, the one or more pH modifierscomprise citric acid (citrate) about 0.1% to about 5% by weight of thecomposition, including each integer within the specified range. In oneembodiment, citrate comprises about 0.1% to about 0.5%; about 0.5% toabout 1%; about 0.25% to about 0.75%; about 0.75% to about 1%; about 1%to about 2%; about 0.5% to about 1.5%; about 0.5% to about 0.75%, orabout 0.25% to about 0.5% by weight of the composition, including eachinteger within the specified ranges. In one aspect, citrate comprisescomprise about 0.1%, about 0.2%, about 0.35, about 0.4%, about 0.5%,about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.2%,about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%,about 1.9%, about 2%, about 2.5%, about 3%, about 4%, or about 5% byweight of the composition.

In one embodiment described herein, the one or more release modifierscomprise a polyethylene oxide polymer, having a molecular weight between6×10⁵ and 7×10⁶ MW, at a weight percentage of about 1% to about 10% byweight of the composition, including each integer within the specifiedrange. In one embodiment, the polyethylene oxide polymer comprises about0.5% to about 2%; about 1% to about 3%; about 2% to about 4%; about 2.5%to about 5%; about 0.5% to about 1%, about 1% to about 2%; about 2% toabout 3%; about 3% to about 4%; or about 4% to about 5% by weight of thecomposition, including each integer within the specified ranges. In oneaspect, the polyethylene oxide polymer, having a molecular weightbetween 1 million and 7 million, comprises about 0.2%, about 0.5%, about1%, about 2%, about 3%, about 4%, about 5%, about 1.1%, about 1.2%,about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%,about 1.9%, about 2.2%, about 2.4%, about 2.6%, about 2.8%, about 2.9%about 3.1%, about 3.2%, about 3.4%, about 3.6%, about 3.8%, about 4.1%,about 4.2%, about 4.4%, about 4.6%, about 4.8%, about 5.5%, about 6%,about 7%, about 8%, about 9%, or about 10% by weight of the composition.

In another embodiment described herein, the sweetener comprises maltitol(e.g., Lycasin® 80/55) at a weight percentage of about 10% to about 60%,by weight of the composition, including each integer within thespecified range. In one embodiment, maltitol comprises about 40% toabout 60%; about 5% to about 20%; about 30% to about 45% by weight ofthe composition, including each integer within the specified ranges. Inone embodiment, maltitol comprise about 5%, about 7.5%, about 10%, about12%, about 14% about 16%, about 18%, about 20%, about 22%, about 24%;about 26%, about 28%, about 30%, about 32%, about 34%, about 35%, about36%, about 38%, about 40%, about 41%, about 42%, about 44% about 45%,about 46%, about 48%, about 50%, about 52%, about 54%, about 56%, about58%, or about 60% by weight of the composition.

In another embodiment described herein, the sweetener comprises xylitol(e.g., Xylisorb 300®) at a weight percentage of about 1% to about 10% byweight of the composition, including each integer within the specifiedrange. In one embodiment, xylitol comprises about 1% to about 5%, about0.5% to about 4%, about 1% to about 3.5%; about 1.5% to about 3%, about2.5% to about 5%; or about 2.5% to about 3.5% by weight of thecomposition, including each integer within the specified ranges. In oneaspect, xylitol comprises about 1%, about 1.5%, about 2%, about 2.5%,about 3%, about 3.5%, about 3.6%, about 4%, about 4.3%, about 4.5%, orabout 5% by weight of the composition.

In another embodiment described herein, the sweetener comprisessucralose comprise a weight percentage of about 0.1% to about 2% byweight of the composition, including each integer within the specifiedrange. In one embodiment, sucralose comprises about 0.1% to about 0.2%;about 0.2% to about 0.3%; about 0.3% to about 0.4%; about 0.25% to about0.4%; or about 0.2% to about 0.5% by weight of the composition,including each integer within the specified ranges. In one aspect,sucralose comprises about 0.2%, about 0.3%, about 0.4%, or about 0.5% byweight of the composition.

In one embodiment described herein, the one or more solubilizing agentscomprise polysorbate 80 at a weight percentage of about 0.1% to about 1%by weight of the composition, including each integer within thespecified range. In one embodiment, polysorbate 80 comprises about 0.2%to about 1%; about 0.3% to about 0.8%; about 0.3% to about 0.5%; about0.6% to about 0.8%; 0.35% to about 0.45%; or about 0.65% to about 0.75%by weight of the composition including each integer within the specifiedranges. In one aspect, polysorbate 80 comprises comprise about 0.1%,about 0.2, about 0.3, about 0.35, about 0.4%, about 0.45%, about 0.5%,about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about 1%, by weightof the composition.

In another embodiment described herein, the solvent comprises water at aweight percentage of about 5% to about 30% by weight of the composition,including each integer within the specified range. In anotherembodiment, water comprises 5% to about 20%; about 10% to about 15%;about 10% to about 20%; about 15% to about 20%; about 15% to about 25%;about 15% to about 30%; about 20% to about 25%; about 20% to about 30%;or about 25% to about 30% by weight of the composition, including eachinteger within the specified ranges. In one aspect, water comprisesabout 5%, about 7.5%, about 10%, about 11%, about 12%, about 13%, about14%, about 15%, about 16%, about 17%. about 18%, about 19%, about 20%,about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about27%, about 28%, about 29%, or about 30% by weight of the composition.

In another embodiment described herein, the active pharmaceuticalingredient comprises fluticasone or a pharmaceutically acceptable saltthereof at a weight percentage of about 0.005% to about 5% by weight ofthe composition, including each integer within the specified range. Inone embodiment, fluticasone comprises about 0.005 to about 0.01%; about0.01% to about 0.05%; about 0.01% to about 0.025%; about 0.025% to about0.1%; about 0.05% to about 0.1%; about 0.016% to about 0.032%; about0.02% to about 0.04%; about 0.02% to about 0.05%; about 0.01% to about0.04%; or about 0.02% to about 0.04% by weight of the composition,including each integer within the specified ranges. In one aspect,fluticasone comprises about 0.01%, about 0.016%, about 0.02%, about0.025%, about 0.03%, about 0.032%, about 0.04%, about 0.05%, about0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%,about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%,about 0.9%, or about 1% by weight of the composition.

In another embodiment described herein, the second active pharmaceuticalingredient comprises lidocaine, prilocaine, or a combination thereof, ora pharmaceutically acceptable salt thereof at a weight percentage ofabout 0.5% to about 10% by weight of the composition, including eachinteger within the specified range. In one embodiment, fluticasonecomprises about 0.5 to about 1%; about 1% to about 1.5%; about 1% toabout 3%; about 1% to about 5%; about 2% to about 5%; about 3% to about5%; about 4% to about 5%; about 0.5% to about 5%; about 2.5% to about5%; or about 0.5% to about 2.5% by weight of the composition, includingeach integer within the specified ranges. In one aspect, fluticasonecomprises about 0.5%, about 0.75%, about 1%, about 1.5%, about 2%, about2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%,about 7%, about 8%, about 9%, or about 10% by weight of the composition.

In another embodiment described herein, the pharmaceutical compositiondescribed herein comprises one or more optional pharmaceuticallyacceptable excipients. In one embodiment the excipient comprises anopacifier such as titanium dioxide at a weight percentage of about 0.2%to about 2%, including each integer within the specified range. Inanother embodiment, the excipient comprises one or more coloring agentsat a weight percentage of about 0.0001% to about 0.5%, including eachinteger within the specified range. In another embodiment, the excipientcomprises one or more flavor at a weight percentage of about 0.1% toabout 4%, including each integer within the specified range. In anotherembodiment, the pharmaceutical composition comprises a combination ofexcipients, including opacifiers, coloring agents, or flavors.

Additional pharmaceutical excipients useful for the pharmaceuticalcomposition as described herein include, for example, the following:acidifying agents (acetic acid, glacial acetic acid, citric acid,fumaric acid, hydrochloric acid, diluted hydrochloric acid, malic acid,nitric acid, phosphoric acid, diluted phosphoric acid, sulfuric acid,tartaric acid); alkalizing agents (ammonia solution, ammonium carbonate,diethanolamine, diisopropanolamine, potassium hydroxide, sodiumbicarbonate, sodium borate, sodium carbonate, sodium hydroxide,trolamine); antifoaming agents (dimethicone, simethicone); antimicrobialpreservatives (benzalkonium chloride, benzalkonium chloride solution,benzethonium chloride, benzoic acid, benzyl alcohol, butylparaben,cetylpyridinium chloride, chlorobutanol, chlorocresol, cresol,dehydroacetic acid, ethylparaben, methylparaben, methylparaben sodium,phenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuricnitrate, potassium benzoate, potassium sorbate, propylparaben,propylparaben sodium, sodium benzoate, sodium dehydroacetate, sodiumpropionate, sorbic acid, thimerosal, thymol); antioxidants (ascorbicacid, ascorbyl palmitate, butylated hydroxyanisole, butylatedhydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate,sodium formaldehyde sulfoxylate, sodium metabisulfite, sodiumthiosulfate, sulfur dioxide, tocopherol, tocopherols excipient);buffering agents (acetic acid, ammonium carbonate, ammonium phosphate,boric acid, citric acid, lactic acid, phosphoric acid, potassiumcitrate, potassium metaphosphate, potassium phosphate monobasic, sodiumacetate, sodium citrate, sodium lactate solution, dibasic sodiumphosphate, monobasic sodium phosphate); chelating agents (edetatedisodium, ethylenediaminetetraacetic acid and salts, edetic acid);coating agents (sodium carboxymethylcellulose, cellulose acetate,cellulose acetate phthalate, ethylcellulose, gelatin, pharmaceuticalglaze, hydroxypropyl cellulose, hydroxypropyl methylcellulose,hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer,methylcellulose, polyvinyl acetate phthalate, shellac, sucrose, titaniumdioxide, carnauba wax, microcrystalline wax, zein); colorants (caramel,red, yellow, black or blends, ferric oxide); complexing agents(ethylenediaminetetraacetic acid and salts (EDTA), edetic acid, gentisicacid ethanolamide, oxyquinoline sulfate); desiccants (calcium chloride,calcium sulfate, silicon dioxide); emulsifying and/or solubilizingagents (acacia, cholesterol, diethanolamine (adjunct), glycerylmonostearate, lanolin alcohols, mono- and di-glycerides,monoethanolamine (adjunct), lecithin, oleic acid (adjunct), oleylalcohol (stabilizer), poloxamer, polyoxyethylene 50 stearate, polyoxyl35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleylether, polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate20, polysorbate 40, polysorbate 60, polysorbate 80, diacetate,monostearate, sodium lauryl sulfate, sodium stearate, sorbitanmonolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitanmonostearate, stearic acid, trolamine, emulsifying wax); filtering aids(powdered cellulose, purified siliceous earth); flavors and perfumes(anethole, benzaldehyde, ethyl vanillin, menthol, methyl salicylate,monosodium glutamate, orange flower oil, peppermint, peppermint oil,peppermint spirit, rose oil, stronger rose water, thymol, tolu balsamtincture, vanilla, vanilla tincture, vanillin); humectants (glycerol,hexylene glycol, sorbitol); plasticizers (e.g., castor oil, diacetylatedmonoglycerides, diethyl phthalate, glycerol, mono- and di-acetylatedmonoglycerides, propylene glycol, triacetin, triethyl citrate); polymers(e.g., cellulose acetate, alkyl celluloses, hydroxyalkyl, acrylicpolymers and copolymers); solvents (acetone, alcohol, diluted alcohol,amylene hydrate, benzyl benzoate, butyl alcohol, carbon tetrachloride,chloroform, corn oil, cottonseed oil, ethyl acetate, glycerol, hexyleneglycol, isopropyl alcohol, methyl alcohol, methylene chloride, methylisobutyl ketone, mineral oil, peanut oil, propylene carbonate, sesameoil, water for injection, sterile water for injection, sterile water forirrigation, purified water); Sorbents (powdered cellulose, charcoal,purified siliceous earth); carbon dioxide sorbents (barium hydroxidelime, soda lime); stiffening agents (hydrogenated castor oil,cetostearyl alcohol, cetyl alcohol, cetyl esters wax, hard fat,paraffin, polyethylene excipient, stearyl alcohol, emulsifying wax,white wax, yellow wax); Suspending and/or viscosity-increasing agents(acacia, agar, alginic acid, aluminum monostearate, bentonite, purifiedbentonite, magma bentonite, carbomer, carboxymethylcellulose calcium,carboxymethylcellulose sodium, carboxymethylcellulose sodium 12,carrageenan, microcrystalline and carboxymethylcellulose sodiumcellulose, dextrin, gelatin, guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesiumaluminum silicate, methylcellulose, pectin, polyethylene oxide,polyvinyl alcohol, povidone, alginate, silicon dioxide, colloidalsilicon dioxide, sodium alginate, tragacanth, xanthum gum); sweeteningagents (aspartame, dextrates, dextrose, excipient dextrose, fructose,mannitol, saccharin, calcium saccharin, sodium saccharin, sorbitol,solution sorbitol, sucrose, compressible sugar, confectioner's sugar,syrup); tablet binders (acacia, alginic acid, sodiumcarboxymethylcellulose, microcrystalline cellulose, dextrin,ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropylmethylcellulose, methylcellulose, polyethylene oxide, povidone,pregelatinized starch, syrup); tablet and/or capsule diluents (calciumcarbonate, dibasic calcium phosphate, tribasic calcium phosphate,calcium sulfate, microcrystalline cellulose, powdered cellulose,dextrates, dextrin, dextrose excipient, fructose, kaolin, lactose,mannitol, sorbitol, starch, pregelatinized starch, sucrose, compressiblesugar, confectioner's sugar); tablet disintegrants (alginic acid,microcrystalline cellulose, croscarmellose sodium, crospovidone,polacrilin potassium, sodium starch glycolate, starch, pregelatinizedstarch); Tablet and/or capsule lubricants (calcium stearate, glycerylbehenate, magnesium stearate, light mineral oil, sodium stearylfumarate, stearic acid, purified stearic acid, talc, hydrogenatedvegetable oil, zinc stearate); tonicity agent (dextrose, glycerol,mannitol, potassium chloride, sodium chloride); vehicle: flavored and/orsweetened (aromatic elixir, compound benzaldehyde elixir, iso-alcoholicelixir, peppermint water, sorbitol solution, syrup, tolu balsam syrup);vehicle: oleaginous (almond oil, corn oil, cottonseed oil, ethyl oleate,isopropyl myristate, isopropyl palmitate, mineral oil, light mineraloil, myristyl alcohol, octyldodecanol, olive oil, peanut oil, persicoil, sesame oil, soybean oil, squalane); vehicle: solid carrier (sugarspheres); vehicle: sterile (bacteriostatic water for injection,bacteriostatic sodium chloride injection); viscosity-increasing (seesuspending agent); water repelling agent (cyclomethicone, dimethicone,simethicone); and/or solubilizing agent (benzalkonium chloride,benzethonium chloride, cetylpyridinium chloride, docusate sodium,nonoxynol 9, nonoxynol 10, octoxynol 9, poloxamer, polyoxyl 35 castoroil, polyoxyl 40, hydrogenated castor oil, polyoxyl 50 stearate,polyoxyl 10 oleyl ether, polyoxyl 20, cetostearyl ether, polyoxyl 40stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate80, sodium lauryl sulfate, sorbitan monolaurate, sorbitan monooleate,sorbitan monopalmitate, sorbitan monostearate, tyloxapol). This list isnot meant to be exclusive, but instead merely representative of theclasses of excipients and the particular excipients that may be used inoral dosage forms as described herein.

In one embodiment described herein, the compositions described hereincomprise one or more active pharmaceutical ingredients. In oneembodiment, one active pharmaceutical ingredient is the only activeingredient in the pharmaceutical composition. In another embodiment, oneor more active pharmaceutical ingredients or drugs are included in thepharmaceutical composition. In another embodiment, one or more activepharmaceutical ingredients or drugs are included in a solid orsemi-solid pharmaceutical composition comprising a soft lozenge.

In one embodiment, the compositions described herein comprise one ormore active pharmaceutical ingredients useful for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of esophagitis, eosinophilic esophagitis,esophageal inflammation, acid reflux, dysphagia, odynophagia, ulcers,heart burn, chest pain, abdominal pain, nausea, vomiting, coughing, sorethroat, decrease in appetite or failure to thrive.

In one embodiment described herein, the active pharmaceutical ingredientcomprises one or more corticosteroids. In one embodiment, the one ormore corticosteroids include but are not limited to alclometasone,amcinonide, beclometasone, betamethasone, budesonide, ciclesonide,clobetasol, clobetasone, clocortolone, cloprednol, cortivazol,deflazacort, deoxycorticosterone, desonide desoximetasone,dexamethasone, diflorasone, diflucortolone, difluprednate, fluclorolone,fludrocortisone, fludroxycortide, flumetasone, flunisolide, fluocinoloneacetonide, fluocinonide, fluocortin, fluocortolone, fluorometholone,fluperolone, fluticasone, fluticasone propionate, fluprednidene,formocortal, halcinonide, halometasone, hydrocortisone aceponate,hydrocortisone buteprate, hydrocortisone butyrate, loteprednol,medrysone, meprednisone, methylprednisolone, methylprednisoloneaceponate, mometasone furoate, paramethasone, prednicarbate, prednisone,prednisolone, prednylidene, rimexolone, tixocortol, triamcinolone andulobetasol, or combinations thereof, pharmaceutically acceptable saltsor esters thereof.

In one embodiment described herein, the active pharmaceutical ingredientcomprises one or more corticosteroid, including but not limited to,fluticasone, budesonide, prednisone, or combinations thereof. In anotheraspect, the active pharmaceutical ingredient comprises budesonide. Inone aspect the active pharmaceutical ingredient comprises fluticasone.In another aspect, the active pharmaceutical ingredient comprisesfluticasone propionate.

In another embodiment, the active pharmaceutical ingredients describedherein may comprise pharmaceutically acceptable salts of any of theabove mentioned active drug substances. The term “pharmaceuticallyacceptable salts” of an active pharmaceutical ingredient includes alkalimetal salts such as, for example, sodium or potassium salts, alkalineearth metal salts such as, for example, calcium and magnesium salts, andsalts with organic or inorganic acid such as, for example, hydrochloricacid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid,citric acid, formic acid, maleic acid, succinic acid, tartaric acid,methanesulphonic acid, toluenesulphonic acid etc. In another embodiment,the active pharmaceutical ingredient may also be in the form ofpharmaceutically acceptable salts, uncharged or charged molecules,molecular complexes, solvates, or anhydrates thereof, and, if relevant,single isomers, enantiomers, racemic mixtures, or mixtures thereof.

In another embodiment, the active pharmaceutical ingredient may be inany of its crystalline, polymorphous, semi-crystalline, amorphous orpolyamorphous forms or mixtures thereof.

In one embodiment described herein, the pharmaceutical composition is asoft lozenge dosage form. The soft lozenge comprises a solid orsemisolid matrix encapsulated by a gelatinous shell. In one embodimentdescribed herein, the soft lozenge dosage form comprises about 0.5 mg or1.0 mg of corticosteroid per dose. This comprises 0.016% or 0.032% byweight of a 3162.7 mg soft lozenge dosage form as described herein.Assuming an average body mass of 70 kg, the soft lozenge dosage formsprovide a dose of 7.14 μg corticosteroid per kg body mass (μg/kg; 0.5 mgdose) or 14.3 μg/kg (1.0 mg dose).

In another embodiment described herein, the pharmaceutical compositionis a liquid dosage form. The liquid dosage form can comprise asuspension, syrup, elixir or concentrate. In one embodiment describedherein the liquid dosage from comprises about 0.5 mg or 1.0 mg ofcorticosteroid per dose. A typical dose of a liquid dosage formcomprises about 1 mL to about 20 mL of liquid, including all integerswithin the specified range.

The exact dosage will depend upon the route of administration, the formin which the composition is administered, the subject to be treated, theage, body weight/height of the subject to be treated, and the preferenceand experience of the attending physician. In certain embodiments, theoptimal concentration of the corticosteroid in the composition dependsupon the specific corticosteroid used, the characteristics of thepatient, and the nature of the inflammation for which the treatment issought. In various embodiments, these factors are determined by those ofskill in the medical and pharmaceutical arts in view of the presentdisclosure.

In one embodiment described herein the pharmaceutical compositioncomprises one or more corticosteroids comprising a therapeuticallyeffective dose. A therapeutically effective dose comprises an amount ofone or more corticosteroids that results in a degree of amelioration ofsymptoms or inflammation relative to the status of such symptoms orinflammation prior to treatment. In one embodiment, the amount of one ormore corticosteroids used in a composition or in a method describedherein is from about 7 μg/kg to about 70 μg/kg of body mass per day.

In one embodiment, the amount of corticosteroid used in a method, in acomposition, or in a dose of a composition described herein comprisesabout 500 μg to about 2 mg, 500 μg to about 1 mg, about 1 mg to about 2mg, about 1 mg, about 3 mg, about 1 mg to about 4 mg, about 1 mg toabout 5 mg, or any amount suitable. In one embodiment, the dosage isprovided in a volume that treats the esophagus with an effective amount.In one embodiment the effective amount is about 0.5 mg, about 1 mg,about 1.5 mg, or about 2 mg of a corticosteroid.

The dosage may, for example, be administered at least once a day, e.g.,in five, four, three, two, or one dose a day. In one illustrativeexample, the dose is provided once a day. In specific embodiments,administration of any composition described herein (e.g., for thetreatment of gastrointestinal or esophageal inflammation includingeosinophilic esophagitis) is once a day. In other specific embodiments,administration (e.g., for the treatment of gastrointestinal oresophageal inflammation including eosinophilic esophagitis) is b.i.d. Instill other embodiments, administration (e.g., for the treatment ofgastrointestinal or esophageal inflammation including eosinophilicesophagitis) is t.i.d. In another embodiment, administration (e.g., forthe treatment of gastrointestinal or esophageal inflammation includingeosinophilic esophagitis) is q.i.d. In another embodiment, the dose isadministered at night. In another aspect, the dose is administered about30 minutes prior to bed, with no food or water given afteradministration of the compositions herein. In another embodiment, thedose is administered prior to bedtime, wherein after administration ofthe composition, the patient or individual is in a substantially supineposition for at least 30 minutes, at least 1 hour, at least 2 hours, atleast 4 hours, at least 8 hours, about 30 minutes to about 8 hours,about 30 minutes to about 4 hours, about 1 hour to about 8 hours, or,about 1 hour to about 6 hours. In some embodiments provided herein, thedose is administered prior to the individual being in a substantiallysupine position for at least 30 minutes, at least 1 hour, at least 2hours, at least 4 hours, at least 8 hours, about 30 minutes to about 8hours, about 30 minutes to about 4 hours, about 1 hour to about 8 hours,or, about 1 hour to about 6 hours. In specific embodiments, acorticosteroid or composition is administered according to any methoddescribed herein, wherein administration of the corticosteroid orcomposition is once a day, no more than once a day, more than once aday, twice a day, two to four times a day, three times a day, or fourtimes a day. In some embodiments, the administration of thecorticosteroid or composition provided herein is administered at night,e.g., not more than once a day at night.

In one embodiment described herein, the corticosteroid is present in apharmaceutical composition described herein in any effective amount. Insome embodiments, an effective amount is an amount sufficient to reduceinflammation or symptoms of inflammation associated with an allergic orcaustic inflammatory disorder or condition of the gastrointestinal tract(e.g., the esophagus) as compared to the level of inflammation orsymptoms of inflammation associated with an inflammatory disease priorto administration of the effective amount. In certain embodiments,effective amount is an amount sufficient to maintain a reduction ininflammation or symptoms of inflammation achieved in any mannerincluding, but not limited to, by the administration of an effectiveamount sufficient to achieve such a reduction in inflammation.

In one embodiment, the effective amount is about 0.5 mg to about 5 mg,about 0.5 mg to about 1 mg, about 0.5 mg to about 2 mg, about 0.5 mg toabout 3 mg; about 0.5 mg to about 4 mg; about 1 mg to about 5 mg, about1 mg to about 2 mg, about 1 mg to about 3 mg, about 1 mg to about 4 mg,about 2 mg to about 3 mg, about 2 mg to about 4 mg, about 2 mg to about5 mg, about 3 mg to about 4 mg, about 3 mg to about 5 mg, or about 4 mgto about 5 mg.

In another embodiment, the effective amount of corticosteroid is about0.25 mg, about 0.5 mg, about 1 mg., about 1.5 mg., about 2 mg., about2.5 mg., about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, or about 5mg, of corticosteroid.

In another embodiment, the corticosteroid is present in a pharmaceuticalcomposition at any concentration suitable for providing atherapeutically effective amount of corticosteroid to a surface of thegastrointestinal tract (e.g., the surface of the esophagus), e.g., at adosage of about 0.01 mg to about 2 mg of composition. In anotherembodiment, the corticosteroid is present in a pharmaceuticalcomposition at a dose of about 0.5 mg to about 1 mg, about 0.5 mg toabout 1.5 mg, about 0.5 mg to about 2 mg, about 0.5 mg to about 2.5 mg,about 0.5 mg to about 3 mg, about 0.5 mg to about 3.5 mg, about 0.5 toabout 4 mg, about 0.5 to about 4.5 mg, or about 0.5 mg to about 5 mg. Inanother embodiment, the corticosteroid is present in a pharmaceuticalcomposition at a dose of about 0.5 mg to about 1 mg. In anotherembodiment, any composition described herein comprises an amount or doseof corticosteroid sufficient to provide about 0.5 mg to about 5 mg ofcorticosteroid per day, about 0.5 mg to about 2 mg of corticosteroid perday, about 1 mg to about 2 mg of corticosteroid per day, about 2 mg toabout 3 mg of corticosteroid per day, about 3 mg to about 4 mg ofcorticosteroid per day, about 4 mg to about 5 mg of corticosteroid perday, or about 5 mg of corticosteroid per day.

In another embodiment described herein, the therapeutically effectivedose is about 2 mg of corticosteroid per day, administered b.i.d orq.i.d.

In another embodiment described herein, the dosage form can beadministered, for example, 1×, 2×, 3×, 4×, 5×, 6×, 7×, or 8×, per day.One or more dosage form can be administered, for example, for 1, 2, 3,4, 5, 6, 7 days, or even longer. One or more dosage forms can beadministered, for example, for 1, 2, 3, 4 weeks, or even longer. One ormore dosage forms can be administered, for example, for 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12 months, or even longer. One or more dosage formscan be administered until the patient, subject, mammal, mammal in needthereof, human, or human in need thereof, does not require treatment,prophylaxis, or amelioration of any disease or condition such as, forexample, inflammation or pain. In some aspects, the dosage form may beco-administered with other pharmaceutical compositions until thepatient, subject, mammal, mammal in need thereof, human, or human inneed thereof, does not require treatment, prophylaxis, or ameliorationof any disease or condition including but not limited to inflammation orpain.

In another embodiment described herein, the dosage form dissolvesintra-orally over a period of time comprising about 30 seconds to about2 minutes, about 1 minute to about 5 minutes, about 5 minutes to about10 minutes, about 10 minutes to about 15 minutes, about 10 minutes toabout 20 minutes, about 15 minutes to about 20 minutes, about 20 minutesto about 30 minutes, about 20 minutes to about 45 minutes, about 30minutes to about 45 minutes, about 30 minutes to about 1 hour, about 45minutes to about 60 minutes, about 45 minutes to about 75 minutes, about60 minutes to about 75 minutes, or about 60 minutes to about 90 minutes.

In another embodiment described herein, the dosage form dissolves invitro in aqueous media at neutral pH over a period of time comprisingabout 30 seconds to about 2 minutes, about 1 minute to about 5 minutes,about 5 minutes to about 10 minutes, about 10 minutes to about 15minutes, about 10 minutes to about 20 minutes, about 15 minutes to about20 minutes, about 20 minutes to about 30 minutes, about 20 minutes toabout 45 minutes, about 30 minutes to about 45 minutes, about 30 minutesto about 1 hour, about 45 minutes to about 60 minutes, about 45 minutesto about 75 minutes, about 60 minutes to about 75 minutes, or about 60minutes to about 90 minutes.

In another embodiment, the dosage form has an in vitro dissolution ratein a neutral aqueous media (e.g., pH 7.4) of about 5% to about 50% afterabout 2 minutes to about 40 minutes, including each integer within thespecified ranges of dissolution and time. In one aspect, the in vitrodissolution rate in a neutral aqueous media (e.g., pH 7.4) is about 50%after about 2 minutes. In one aspect, the in vitro dissolution rate in aneutral aqueous media (e.g., pH 7.4) is about 50% after about 2.5minutes. In one aspect, the in vitro dissolution rate in a neutralaqueous media (e.g., pH 7.4) is about 50% after about 5 minutes. In oneaspect, the in vitro dissolution rate in a neutral aqueous media (e.g.,pH 7.4) is about 50% after about 7.5 minutes. In one aspect, the invitro dissolution rate in a neutral aqueous media (e.g., pH 7.4) isabout 50% after about 10 minutes. In one aspect, the in vitrodissolution rate in a neutral aqueous media (e.g., pH 7.4) is about 50%after about 12.5 minutes. In one aspect, the in vitro dissolution ratein a neutral aqueous media (e.g., pH 7.4) is about 50% after about 15minutes. In one aspect, the in vitro dissolution rate in a neutralaqueous media (e.g., pH 7.4) is about 50% after about 20 minutes. In oneaspect, the in vitro dissolution rate in a neutral aqueous media (e.g.,pH 7.4) is about 50% after about 25 minutes. In one aspect, the in vitrodissolution rate in a neutral aqueous media (e.g., pH 7.4) is about 50%after about 30 minutes.

In another embodiment described herein, the dosage form releases theactive ingredient over a period of time comprising about 30 seconds toabout 2 minutes, about 1 minute to about 5 minutes, about 5 minutes toabout 10 minutes, about 10 minutes to about 15 minutes, about 10 minutesto about 20 minutes, about 15 minutes to about 20 minutes, about 20minutes to about 30 minutes, about 20 minutes to about 45 minutes, about30 minutes to about 45 minutes, about 30 minutes to about 1 hour, about45 minutes to about 60 minutes, about 45 minutes to about 75 minutes,about 60 minutes to about 75 minutes, or about 60 minutes to about 90minutes.

In another embodiment described herein, the dosage form is in contactwith the oral and esophageal mucosa for a period of time comprisingabout 30 seconds to about 45 minutes, including all integers within thespecified range. In one aspect, the dosage form is in contact with theoral and esophageal mucosa for a period of time comprising about 30seconds, about 1 minutes, about 2 minutes, about 3 minutes, about 4minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8minutes, about 9 minutes, about 10 minutes, about 11 minutes, about 12minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90minutes, or even longer.

In another embodiment described herein, the dosage form is in contactwith the oral and esophageal mucosa for a period of time comprising atleast about 30 seconds to about 45 minutes, including all integerswithin the specified range. In one aspect, the dosage form is in contactwith the oral and esophageal mucosa for a period of time comprising atleast about 30 seconds, about 1 minutes, about 2 minutes, about 3minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 11minutes, about 12 minutes, about 15 minutes, about 20 minutes, about 25minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85minutes, about 90 minutes, or even longer.

In another embodiment described herein, the dosage form is in contactwith the oral and esophageal mucosa for a period of time comprisingabout 30 seconds to about 90 minutes including all integers within thespecified range. In one aspect, the dosage form is in contact with theoral and esophageal mucosa for a period of time comprising about 30seconds to about 2 minutes, about 1 minute to about 5 minutes, about 1minutes to about 10 minutes, about 1 minute to about 15 minutes, about 1minute to about 20 minutes, about 1 minute to about 20 minutes, about 1minute to about 30 minutes, about 1 minute to about 45 minutes, about 1minute to about 1 hour, about 1 minute to about 75 minutes, or about 1minute to about 90 minutes.

In another embodiment described herein, the dosage form is in contactwith the oral and esophageal mucosa for a period of time comprising atleast about 30 seconds to about 90 minutes including all integers withinthe specified range. In one aspect, the dosage form is in contact withthe oral and esophageal mucosa for a period of time comprising at leastabout 30 seconds to about 2 minutes, about 1 minute to about 5 minutes,about 5 minutes to about 10 minutes, about 10 minutes to about 15minutes, about 10 minutes to about 20 minutes, about 15 minutes to about20 minutes, about 20 minutes to about 30 minutes, about 20 minutes toabout 45 minutes, about 30 minutes to about 45 minutes, about 30 minutesto about 1 hour, about 45 minutes to about 60 minutes, about 45 minutesto about 75 minutes, about 60 minutes to about 75 minutes, or about 60minutes to about 90 minutes.

Another embodiment described herein is a topical, non-systemic,slow-release oral pharmaceutical composition suitable for chewing,sucking, buccal dissolution or swallowing as described herein fortreating, retarding the progression of, prophylaxis of, delaying theonset of, ameliorating, reducing the symptoms of, or promoting health,including but not limited to of one or more of esophageal, oral, orbuccal inflammation, eosinophilic esophagitis, oral lichen planus,aphthous stomatitis, odynophagia, acid reflux, dysphagia, oral,esophageal or peptic ulcers, heart burn, chest pain, abdominal pain,nausea, vomiting, coughing, sore throat, decrease in appetite, orfailure to thrive.

Another embodiment described herein is a method for treating, retardingthe progression of, prophylaxis of, delaying the onset of, ameliorating,reducing the symptoms of, or promoting health of one or more ofesophageal, oral, or buccal inflammation, eosinophilic esophagitis, orallichen planus, aphthous stomatitis, odynophagia, acid reflux, dysphagia,oral, esophageal or peptic ulcers, heart burn, chest pain, abdominalpain, nausea, vomiting, coughing, sore throat, decrease in appetite, orfailure to thrive, comprising administering to a subject in need thereofan oral pharmaceutical composition suitable for chewing, sucking, orbuccal dissolution as described herein.

Another embodiment described herein is a topical, non-systemic,slow-release pharmaceutical composition suitable for chewing, sucking,buccal dissolution or swallowing as described herein for treating asubject suffering from one or more of oral or esophageal inflammation,eosinophilic esophagitis, inflammatory bowel disease involving theesophagus, oral lichen planus, aphthous stomatitis, Crohn's disease,esophageal inflammation secondary to caustic/irritant ingestion,recurrent esophageal strictures of any cause and including irritantingestion, pill-induced esophagitis, systemic diseases, congentialdiseases, epidermolysis bullosa, trauma, or post-surgery inflammation.

Another embodiment described herein is a method for treating a subjectsuffering from oral or esophageal inflammation, eosinophilicesophagitis, inflammatory bowel disease involving the esophagus, orallichen planus, aphthous stomatitis, Crohn's disease, esophagealinflammation secondary to caustic/irritant ingestion, recurrentesophageal strictures of any cause and including irritant ingestion,pill-induced esophagitis, systemic diseases, congential diseases,epidermolysis bullosa, trauma, or post-surgery inflammation, includingcomprising administering to the subject in need thereof an topical,non-systemic, slow-releasing oral pharmaceutical composition suitablefor chewing, sucking, buccal dissolution, or swallowing as describedherein.

Another embodiment described herein is a topical, non-systemic,slow-releasing oral pharmaceutical composition suitable for chewing,sucking, buccal dissolution, or swallowing as described herein fortreating disease, allergic, idiopathic, immunogenic, traumatic, causticor general inflammation of the oral cavity, esophagus, or uppergastrointestinal tract, or a symptom thereof comprising about 0.5 mg toabout 5 mg of corticosteroid, about 0.5 mg to about 1 mg ofcorticosteroid, about 1 mg to about 2 mg of corticosteroid, about 2 mgto about 3 mg of corticosteroid, about 3 mg to about 4 mg ofcorticosteroid, or about 4 mg to about 5 mg of corticosteroid.

Another embodiment described herein is a method for treating disease,allergic, idiopathic, immunogenic, traumatic, caustic or generalinflammation of the oral cavity, esophagus, or upper gastrointestinaltract, or a symptom thereof, by administering a sufficient amount of apharmaceutical composition suitable for chewing, sucking, or buccaldissolution as described herein to provide about 0.5 mg to about 5 mg ofcorticosteroid per day, about 0.5 mg to about 1 mg of corticosteroid perday, about 1 mg to about 2 mg of corticosteroid per day, about 2 mg toabout 3 mg of corticosteroid per day, about 3 mg to about 4 mg ofcorticosteroid per day, or about 4 mg to about 5 mg of corticosteroidper day to an individual in need thereof.

Initial treatment may continue, for example, for about 3 days to 2 weeksfor an acute condition, or about 4 weeks to about 16 weeks for a chroniccondition, or about 8 weeks to about 12 weeks for a chronic condition.Longer therapy may also be needed, such as, for example, therapy similarto chronic therapy for persistent asthma. Patients may, for example, betreated for up to 6 months, or up to one year. Maintenance treatment canlast up to or longer than one year. Patients may be treated on amaintenance basis or on an as needed basis during a problematic episode,depending on the severity of the condition. Patients can also be treatedon a rotating treatment basis, where treatment is provided for a periodof time and then the patient is taken off of the drug for a periodbefore treatment resumes again. When off the drug, the patient may begiven no treatment, treatment with another medication, or treatment witha reduced dosage. Patients may be given treatment with a higher dose ofthe composition until a desired reduced disease state is achieved, andthen continued on a lower dose of the composition.

Another embodiment described herein comprises administering one or moreof the pharmaceutical compositions or dosage forms described herein incombination with one or more additional active pharmaceuticalingredients. Such combinations may be formulated into a single dosageform or alternatively co-administered as separate dosage forms in atreatment regimen. Co-administration may be simultaneously or at adifferent time. Suitable combinations include administering one or morecorticosteroids as described herein with one or more antacids, syntheticcorticosteroids, proton pump inhibitors (e.g., H₁ and H₂ antagonists),β₂ adrenergic receptor agonists, anticholinergic bronchodilators,antihistamines, leukotriene receptor antagonists, interleukin-5antibodies, anti-IgE antibodies, anti-TNF antibodies, purine analogues,non-steroidal anti-inflamatory drugs (NSAIDS), one or more antibiotics,or combinations thereof. In one embodiment the pharmaceuticalcompositions described herein can be combined with one or more ofantacids (e.g., calcium hydroxide, magnesium hydroxide, alluminumhydroxide, sodium bicarbonate, calcium carbonate, bismuth subsalicylate, or others; Maalox, Mylanta, Gaviscon, Kaopectate,Pepto-Bismol) sucralfate, esomeprazole, omeprazole, lansoprazole,dexlansoprazole, esomeprazole, pantoprazole, rabeprazole, ilaprazole,cimetidine, ranitidine, famotidine, lafutidine, nizatidine, roxatidine,tiotidine, salmeterol, albuterol, aclidinium, ipratropium, tiotropium,umeclidinium, acrivastine, azelastine, bilastine, brompheniramine,buclizine, bromodiphenhydramine, carbinoxamine, chlorpromazine,cyclizine, chlorphenamine, chlorodiphenhydramine, clemastine,cyproheptadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate,dimetindene, diphenhydramine, doxylamine, ebastine, embramine,fexofenadine, hydroxyzine, loratadine, meclozine, mirtazapine,olopatadine, orphenadrine, phenindamine pheniramine, phenyltoloxamine,promethazine, quetiapine, rupatadine, tripelennamine, triprolidine,clobenpropit, ciproxifan, conessine, thioperamide, montelukast,zafirlukast, pranlukast, mepolizumab, reslizumab, omalizumab,infliximab, azathioprine, 6-mercaptopurine, thioguanine, aspirin(acetylsalicylic acid), ibuprofen, naproxen, ketoprofen, celecoxib,diclofenac, amikacin, gentamicin, kanamycin, neomycin, netilmicin,tobramycin, paromomycin, streptomycin, spectinomycin, geldanamycin,herbimycin, rifaximin, loracarbef, ertapenem, doripenem,imipenem/cilastatin, meropenem, cefadroxil, cefazolin, cefalotin,cefalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime,cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime,ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftarolinefosamil, ceftobiprole, teicoplanin, vancomycin, telavancin, dalbavancin,oritavancin, clindamycin, lincomycin, daptomycin, azithromycin,clarithromycin, dirithromycin, erythromycin, roxithromycin,troleandomycin, telithromycin, spiramycin, aztreonam, furazolidone,nitrofurantoin, linezolid, posizolid, radezolid, torezolid, amoxicillin,ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin,flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin,penicillin G, penicillin V, piperacillin, temocillin, ticarcillin,amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam,ticarcillin/clavulanate, bacitracin, colistin, polymyxin B,ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin,lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin,trovafloxacin, grepafloxacin, sparfloxacin, temafloxacin, mafenide,sulfacetamide, sulfadiazine, silver sulfadiazine, sulfadimethoxine,sulfamethizole, sulfamethoxazole, sulfanilimide, sulfasalazine,sulfisoxazole, trimethoprim-sulfamethoxazole, sulfamidochrysoidine,demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline,clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide,isoniazid, pyrazinamide, rifampicin, rifabutin, rifapentine,streptomycin, arsphenamine, chloramphenicol, fosfomycin, fusidic acid,metronidazole, mupirocin, platensimycin, quinupristin/dalfopristin,thiamphenicol, tigecycline, tinidazole, trimethoprim, or combinationsthereof.

In another embodiment the pharmaceutical compositions described hereincan be administered in combination with elimination or elemental diets.In one embodiment, the subject eliminates milk products, eggs, wheat,soy, peanut/tree nuts, and fish/shellfish from the diet for at least 6weeks. In another embodiment, foods are re-introduced while monitoringsymptoms. Foods most frequently associated with eosinophilic esophagitisin adults were wheat and milk. Gonsalves et al., Gastroenterology142(7):1451-1459 (2012), incorporated herein by reference for thespecific teachings thereof. Elemental diets comprising monomeric foodelements, including amino acids, fats, sugars, vitamins, and minerals,can also be used in combination with the pharmaceutical compositionsdescribed herein. Such elemental diets can reduce the symptoms ofeosinophilic esophagitis. Vashi and Hirano, Curr. Opin. Gastroenterol.29(4):407-415 (2013), incorporated herein by reference for the specificteachings thereof.

In another embodiment, the pharmaceutical composition may contain one ormore active pharmacetical ingredients. For example, the pharmaceuticalcomposition may contain one or more corticosteroids and one or moretopical anesthetics such as lidocaine, prilocaine, or a eutectic mixtureof idocaine/prilocaine, at a concentration of about 2% to about 5% ofanesthetic by weight of the total pharmaceutical composition. Suchpharmaceutical compositions may be used for treating pain associatedwith oral or esophageal inflammation, including but not limited toinfection, trauma, post-surgical inflammation, oral lichen planus, orother painful inflammatory condition or disorder.

Another embodiment described herein is a process of manufacturingpharmaceutical compositions comprising the soft lozenges as describedherein. The process includes preparing the matrix fill composition isprepared by combining gelatin, glycerol, and water and maintaining themixture and adding maltitol syrup to create a fill gel solution;separately, combining water, xylitol, sucralose, and citric acidtogether to create a fill sweetener solution; separately, combining theactive pharmaceutical ingredient (API) and polysorbate 80; combining theAPI and polysorbate 80 with the fill sweetener solution to create an APIsolution; combining the API solution and the fill gel solution; furthermixing the combined API and fill gel solution at least about 65° C.;slowly introducing solid polyethylene oxide into the combined API andfill gel solution and mixing and deaerating at least about 65° C.creating a matrix fill composition. The gel mass is prepared bycombining gelatins, glycerol, and water and maintaining the mixture atleast about 65° C.; adding maltitol syrup to create a shell gelsolution; separately, combining water, xylitol, sucralose, and citricacid together to create a shell sweetener solution; combining the shellsweetener solution and shell gel solution and mixing the combined shellsweetener and shell gel solution at least about 65° C. to create a gelmass. The soft lozenge is prepared by casting the gel mass into shellfilms or ribbons using heat-controlled drums or surfaces; and injectingthe matrix fill solution between the shell ribbons, and creating softlozenges using rotary die technology. Rotary die encapsulation may beperformed using an apparatus as described in U.S. Pat. Nos. 5,459,983;5,146,730; and 6,482,516, each of which are incorporated by referenceherein for such teachings.

Another embodiment described herein includes a process of manufacturingsoft lozenges comprising the pharmaceutical compositions as describedherein. The process includes preparing a gel mass composition comprisingone or more polymers, one or more plasticizers, one or more pHmodifiers, one or more solvents, one or more active pharmaceuticalingredients, and appropriate flavorings, sweeteners, coloring agents, orother excipients; casting the gel mass into films or ribbons usingheat-controlled drums or surfaces; and manufacturing a soft capsulecomprising a matrix fill using rotary die technology. The thickness ofthe films or ribbons that form the soft lozenge is from about 0.010inches (0.254 mm) to about 0.050 inches (1.27 mm), including allintegers within the specified range. The shell thickness can be about0.010 inch (0.254 mm), about 0.015 inch (0.381 mm), about 0.02 in (0.508mm), about 0.03 in (0.762 mm), about 0.04 in (1.02 mm), or about 0.05 in(1.27 mm). In one embodiment, the thickness is about 0.02 inches (0.508mm) to about 0.040 inches (1.02 mm). In one embodiment, the shellthickness is about 0.028 inches (0.711 mm). In another embodiment, theshell thickness is about 0.033 inches (0.838 mm). In another embodiment,the shell thickness is about 0.038 inches (0.965 mm). In someembodiments, the fill of the soft lozenge can comprise the samecomponents of the “shell” and can be injected into the “shell” to form auniform soft lozenge. In other embodiments, the shell can have adifferent formulation as compare to the fill.

In another embodiment described herein, the soft lozenge comprises anouter dimension from about 2 oval to about 30 oval including alliterations of typical soft capsule sizes within the specified range(e.g., 2 oval, 3 oval, 4 oval, 5 oval, 6 oval, 7 oval, 8 oval, 10 oval,12 oval, 16 oval, 20, or 30 oval). In another embodiment describedherein, the soft lozenge comprises an outer dimension from about 2 roundto about 28 round including all iterations of capsule size within thespecified range (e.g., 2 round, 3 round, 4 round, 5 round, 6 round, 7round, 8 round, 10 round, 12 round, 16 round, 20 round or 28 round). Inanother embodiment described herein, the soft lozenge comprises an outerdimension from about 2 oblong to about 22 oblong including alliterations of capsule size within the specified range (e.g., 2 oblong, 3oblong, 4 oblong, 5 oblong, 6 oblong, 7 oblong, 8 oblong, 10 oblong, 11,oblong, 12 oblong, 14 oblong, 16 oblong, 20 oblong, or 22 oblong). SeeRemington's Essentials of Pharmaceutics, Pharmaceutical Press PublishingCompany, London, UK, 1^(st) Edition, 2013, which is incorporated byreference herein for such teachings.

In another embodiment, the pharmaceutical composition described hereinis contained and dispensed from a tamper evident packaging. The term“tamper evident” or “tamper resistant” refers to a packaging of any kindthat readily displays or allows an individual to observe any physicalinterference or manipulation of said packaging. The tamper evidentpackaging provides reasonable evidence to consumers that tampering hasoccurred. The tamper evident packaging additionally contains appropriatelabelling statements describing the features and evidences of the tamperevident packaging. In one aspect, the tamper evident packagingcomprises: bottles, film wrappers, blister or strip packs, bubble packs,heat shrink bands or wrappers, foil, paper, or plastic pouches,container mouth inner seals, tape seals, breakable caps, sealed metaltubes or plastic heat-sealed tubes, sealed cartons, aerosol containers,cans including metal and composite materials, or any combinationthereof. The packaging may also contain instructions for prescribing,instructions for use, warnings, or other appropriate information.

It will be apparent to one of ordinary skill in the relevant art thatsuitable modifications and adaptations to the compositions,formulations, methods, processes, and applications described herein canbe made without departing from the scope of any embodiments or aspectsthereof. The compositions and methods provided are exemplary and are notintended to limit the scope of any of the specified embodiments. All ofthe various embodiments, aspects, and options disclosed herein can becombined in any and all variations or iterations. The scope of thecompositions, formulations, methods, and processes described hereininclude all actual or potential combinations of embodiments, aspects,options, examples, and preferences herein described. The exemplarycompositions and formulations described herein may omit any component,substitute any component disclosed herein, or include any componentdisclosed elsewhere herein. The ratios of the mass of any component ofany of the compositions or formulations disclosed herein to the mass ofany other component in the formulation or to the total mass of the othercomponents in the formulation are hereby disclosed as if they wereexpressly disclosed. Should the meaning of any terms in any of thepatents or publications incorporated by reference conflict with themeaning of the terms used in this disclosure, the meanings of the termsin this disclosure are controlling. Furthermore, the foregoing disclosesand describes exemplary embodiments. All patents and publications citedherein are incorporated by reference herein for the specific teachingsthereof.

EXAMPLES Example 1 Soft Lozenge Compositions

Exemplary soft lozenges were prepared by rotary die encapsulation usingthe respective fill and shell compositions shown in Tables 7-8. Theweight of the fill is 2000 mg and the shell is 1162.7 mg. The totalweight of the soft lozenge is 3162.7 mg. After drying, the final mass ofthe soft lozenge is about 2800 mg. About 300-400 mg of water isevaporated during drying (˜9-10% water lost).

TABLE 7 Exemplary Soft Lozenge Fill Composition Weight PercentIngredient Mass (mg) (%) Gelatin, 150 Bloom 150 7.5 Glycerol 150 7.5Citric Acid 20 1 Mannitol Syrup 1154 57.7 Xylitol (Xylisorb 300 ®) 854.3 Sucralose 6 0.3 Water 433 21.7 Fluticasone 1.8 0.1 TOTAL 2000 100%

TABLE 8 Exemplary Soft Lozenge Shell Composition Weight Ingredient Mass(mg) Percent (%) Gelatin, 150 Bloom 219.9 18.9 Gelatin, 100 Bloom 149.912.9 Gelatin Hydrolysate 27.7 2.4 Glycerol 264.6 22.8 Citric Acid,Anhydrous 6.3 0.5 Maltitol (75% solution; 163.7 14.1 e.g., Lycasin ®80/55) Xylitol (e.g., Xylisorb 300 ®) 29.1 2.5 Sucralose 2.4 0.2 Water286.6 24.6 Titanium Dioxide 12.5 1.1 TOTAL 1162.7 100%

Example 2

Based on the results of solubility and bioavailability testing of theExample 1 formulation (data not shown), a second formulation wasdeveloped that included a solubilizing agent comprising polysorbate 80and release modifier comprising a high molecular weight polyethyleneoxide to further solubilize and control the release of the activepharmaceutical ingredient. Batches of soft lozenges were prepared byrotary die encapsulation using the fill and shell compositions shown inTables 9-10. The total weight of the soft lozenge was 3162.7 mg. Afterdrying, the final mass of the soft lozenge was about 2800 mg. About300-400 mg of water is evaporated during drying (˜9-10% water lost).

TABLE 9 Exemplary Soft Lozenge Fill Composition Ingredient Mass (mg)Weight Percent (%) Gelatin, 150 Bloom 150 7.5 Glycerol 150 7.5Polyethylene Oxide, 7,000,000 MW, 60 3 (e.g., Polyox ® WSR-303) CitricAcid 20 1 Mannitol Syrup 1154 57.7 Xylitol (e.g., Xylisorb 300 ®) 85 4.3Sucralose 6 0.3 Polysorbate 80 (e.g., Tween ® 80) 14 0.7 Water 360 18Fluticasone propionate 1.8 0.1 TOTAL 2000 100%

TABLE 10 Exemplary Soft Lozenge Shell Composition Mass Weight PercentIngredient (mg) (%) Gelatin, 150 Bloom 219.9 18.9 Gelatin, 100 Bloom149.9 12.9 Gelatin Hydrolysate 27.7 2.4 Glycerol 264.6 22.8 Citric Acid,Anhydrous 6.3 0.5 Maltitol (75% solution; e.g., 163.7 14.1 Lycasin ®80/55) Xylitol (e.g., Xylisorb 300 ®) 29.1 2.5 Sucralose 2.4 0.2 Water286.6 24.6 Titanium Dioxide 12.5 1.1 TOTAL 1162.7 100%

Example 3

Exemplary soft lozenges can be prepared by rotary die encapsulationusing the compositions shown in Tables 11-12. The weight of the fill is2000 mg and the shell is 1162.7 mg. The total weight of the soft lozengeis 3162.7 mg. After drying, the final mass of the soft lozenge is about2800 mg. About 300-400 mg of water is evaporated during drying (˜9-10%water lost).

TABLE 11 Exemplary Soft Lozenge Fill Compositions Weight Percent (%) EX1EX2 EX3 EX4 EX5 EX6 EX7 EX8 Ingredient Gelatin, 150 Bloom 7.0 10.0 9.08.0 9.0 10.0 4.5 11.0 Polyethylene Oxide, 7,000,000 1.0 5.0 2.8 3.0 4.14.0 4.3 5.0 MW, (e.g., Polyox ® WSR-303) Glycerol 11.0 10.0 9.0 8.0 7.06.0 5.0 4.0 Citric Acid 5.0 4.3 3.5 3.0 2.0 1.5 1.0 0.5 Maltitol (75%solution; e.g., 34.7 24.7 45.3 54.0 58.2 60.9 70.2 66.3 Lycasin ® 80/55)Xylitol (e.g., Xylisorb 300 ®) 10.0 9.0 6.0 5.5 4.8 3.5 2.0 1.0Sucralose 0.1 2.0 0.6 1.0 1.5 1.8 1.8 2.1 Polysorbate 80 (e.g., Tween ®80) 1.2 1.0 0.8 0.5 0.4 0.3 0.3 0.1 Water 30.0 34.0 23.0 17.0 13.0 12.011.0 10.0 Fluticasone propionate 0.03 0.05 0.08 0.01 0.10 0.05 0.04 0.03TOTAL 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 SubcomponentTotals Film-forming Polymer 7.0 10.0 9.0 8.0 9.0 10.0 4.5 11.0 ReleaseModifier 1.0 5.0 2.8 3.0 4.1 4.0 4.3 5.0 Plasticizer 11.0 10.0 9.0 8.07.0 6.0 5.0 4.0 pH Modifier 5.0 4.3 3.5 3.0 2.0 1.5 1.0 0.5 Sweetener44.8 35.7 51.9 60.5 64.4 66.2 74.0 69.4 Solubilizing Agent 1.2 1.0 0.80.5 0.4 0.3 0.3 0.1 Solvent 30.0 34.0 23.0 17.0 13.0 12.0 11.0 10.0 API0.0 0.1 0.1 0.0 0.1 0.1 0.0 0.0 Relational Ratios API:Total FillComposition 2.5E⁻⁴ 5.0E⁻⁴ 7.5E⁻⁴ 1.0E⁻⁴ 1.0E⁻⁴ 5.0E⁻⁴ 4.0E⁻⁴ 2.5E⁻⁴PEO:Gelatin 0.14 0.50 0.31 0.38 0.46 0.40 0.94 0.45 PEO:Plasticizer 0.090.50 0.31 0.38 0.59 0.67 0.85 1.25

TABLE 12 Exemplary Soft Lozenge Shell Compositions Weight Percent (%)EX1 EX2 EX3 EX4 EX5 EX6 EX7 EX8 Ingredient Gelatin, 150 Bloom 20.0 20.019.0 17.0 15.0 12.0 11.0 10.0 Gelatin, 100 Bloom 10.0 12.0 14.0 12.014.0 14.0 17.0 10.0 Gelatin hydrolysate 0.5 0.5 1.0 2.0 3.0 4.0 5.0 5.0Glycerol 10.0 12.0 15.0 17.0 22.0 25.0 27.0 30.0 Maltitol (75% solution;e.g., 5.0 4.5 4.0 3.0 2.5 1.0 0.8 0.1 Lycasin ® 80/55) Citric Acid 5.010.0 9.2 14.5 12.7 18.9 19.3 20.3 Xylitol 10.0 9.0 7.0 5.0 3.0 1.0 1.58.0 Sucralose 2.5 2.0 1.8 1.5 1.0 0.1 0.4 0.1 Water 35.0 29.0 27.0 26.024.0 22.0 15.0 12.0 Titanium dioxide 0.0 0.0 0.1 0.5 0.8 1.0 1.5 2.5Coloring (FD&C dyes) 0.020 0.010 0.015 0.020 0.020 0.010 0.015 0.020Flavoring (e.g., cherry, orange) 2.0 1.0 2.0 1.5 2.0 1.0 1.5 2.0 TOTAL100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 Subcomponent TotalsFilm-forming Polymers 30.5 32.5 34.0 31.0 32.0 30.0 33.0 25.0Plasticizer 10.0 12.0 15.0 17.0 22.0 25.0 27.0 30.0 pH Modifier 5.0 4.54.0 3.0 2.5 1.0 0.8 0.1 Total Sweetener 17.5 21.0 17.9 21.0 16.7 20.021.2 28.4 Solvent 35.0 29.0 27.0 26.0 24.0 22.0 15.0 12.0 Excipients 2.01.0 2.1 2.0 2.8 2.0 3.0 4.5 Relational Ratios Gelatin:Plasticizer 3.12.7 2.3 1.8 1.5 1.2 1.2 0.8

Example 4

Exemplary soft lozenges can be prepared by rotary die encapsulationusing the fill composition in Table 13 with the shell compositions shownin Tables 10 or 12. The weight of the fill is 2000 mg and the shell is1162.7 mg. The total weight of the soft lozenge is 3162.7 mg. Afterdrying, the final mass of the soft lozenge is about 2800 mg. About300-400 mg of water is evaporated during drying (˜9-10% water lost).

TABLE 13 Exemplary Soft Lozenge Fill Compositions Weight Percent (%) EX1EX2 EX3 EX4 EX5 EX6 EX7 EX8 Ingredient Gelatin, 150 Bloom 7.5 7.5 7.57.5 7.5 7.5 7.5 7.5 Polyethylene Oxide, 4,000,000 — 4.6 — — — — — — MW,(e.g., Polyox ® WSR-303) Polyethylene Oxide, 5,000,000 — — 4.0 3.5 — — —— MW Polyethylene Oxide, 7,000,000 2.8 — — — 4.0 — — 3.2 MW PolyethyleneOxide, 10,000,000 — — — — — 2.5 2.1 — MW Glycerol 7.5 7.5 7.5 7.5 7.57.5 7.5 7.5 Citric Acid 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Maltitol (75%solution; e.g., 57.9 56.1 56.7 57.2 56.7 58.2 58.6 57.5 Lycasin ® 80/55)Xylitol 4.3 4.3 4.3 4.3 4.3 4.3 4.3 4.3 Sucralose 0.3 0.3 0.3 0.3 0.30.3 0.3 0.3 Polysorbate 80 (e.g., Tween ® 80) 0.7 0.7 0.7 0.7 0.7 0.70.7 0.7 Water 18.0 18.0 18.0 18.0 18.0 18.0 18.0 18.0 Fluticasonepropionate 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.025 TOTAL 100.0100.0 100.0 100.0 100.0 100.0 100.0 100.0 Subcomponent TotalsFilm-forming Polymer 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 Release Modifier2.8 4.6 4.0 3.5 4.0 2.5 2.1 3.2 Plasticizer 7.5 7.5 7.5 7.5 7.5 7.5 7.57.5 pH Modifier 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Sweetener 62.5 60.7 61.361.8 61.3 62.8 63.2 62.1 Solubilizing Agent 0.7 0.7 0.7 0.7 0.7 0.7 0.70.7 Solvent 18.0 18.0 18.0 18.0 18.0 18.0 18.0 18.0 API 0.025 0.0250.025 0.025 0.025 0.025 0.025 0.025 Relational Ratios API:Total FillComposition 2.5E⁻⁴ 2.5E⁻⁴ 2.5E⁻⁴ 2.5E⁻⁴ 2.5E⁻⁴ 2.5E⁻⁴ 2.5E⁻⁴ 2.5E⁻⁴PEO:Gelatin 0.373 0.613 0.533 0.467 0.533 0.333 0.280 0.427PEO:Plasticizer 0.373 0.613 0.533 0.467 0.533 0.333 0.280 0.427Gelatin:Plasticizer 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0

Example 5

Exemplary soft lozenges can be prepared by rotary die encapsulationusing compositions shown in Table 14. The weight of the fill is 2000 mgand the shell is 1162.7 mg. The total weight of the soft lozenge is3162.7 mg. After drying, the final mass of the soft lozenge is about2800 mg. About 300-400 mg of water is evaporated during drying (˜9-10%water lost).

TABLE 14 Exemplary Soft Lozenge Total Compositions (Shell and Fill)Weight Percent (%) EX1 EX2 EX3 EX4 EX5 EX6 EX7 EX8 Ingredient Gelatin,150 Bloom 11.70 12.33 11.07 12.65 10.12 7.59 5.06 11.54 Gelatin, 100Bloom 4.74 3.79 5.06 3.16 6.32 9.49 11.38 4.90 Gelatin hydrolysate 0.890.63 0.95 0.32 0.79 0.47 0.89 0.79 PEO, 1 × 10⁶-7 × 10⁶ MW 1.90 1.582.06 2.21 1.96 1.74 1.90 2.02 Glycerol 13.12 12.65 13.28 13.12 12.9613.28 13.03 13.60 Maltitol (e.g., Lycasin ® 80/55) 0.85 0.76 0.95 0.791.26 0.89 0.82 0.79 Citric Acid 41.53 44.24 41.29 42.94 41.46 41.4342.12 41.39 Xylitol 3.64 3.16 3.79 3.48 4.11 3.95 3.64 3.16 Sucralose0.25 0.22 0.28 0.19 0.25 0.22 0.21 0.32 Polysorbate 80 0.44 0.38 0.320.41 0.25 0.47 0.41 0.51 Water 20.49 20.24 20.55 20.39 19.92 20.24 20.0820.55 Fluticasone propionate 0.01 0.02 0.02 0.03 0.05 0.02 0.03 0.02Titanium dioxide 0.38 0.00 0.32 0.25 0.47 0.19 0.40 0.35 Coloring (FD&Cdyes) 6.3E⁻⁴ 0.00 4.7E⁻⁴ 6.3E⁻⁴ 6.3E⁻⁴ 3.2E⁻⁴ 4.7E⁻⁴ 6.3E⁻⁴ Flavoring(e.g., cherry, orange) 0.06 0.00 0.06 0.05 0.06 0.03 0.05 0.06 TOTAL100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 Subcomponent TotalsFilm-forming Polymers 17.33 16.76 17.07 16.13 17.23 17.55 17.33 17.23Release Modifiers 1.90 1.58 2.06 2.21 1.96 1.74 1.90 2.02 Plasticizer13.12 12.65 13.28 13.12 12.96 13.28 13.03 13.60 pH Modifier 0.85 0.760.95 0.79 1.26 0.89 0.82 0.79 Sweetener 45.42 47.62 45.37 46.61 45.8245.60 45.96 44.86 Solubilizing Agent 0.44 0.38 0.32 0.41 0.25 0.47 0.410.51 Solvent 20.49 20.24 20.55 20.39 19.92 20.24 20.08 20.55 API 0.010.02 0.02 0.03 0.05 0.02 0.03 0.02 Excipients 0.44 0.00 0.38 0.30 0.540.22 0.44 0.41 Relational Ratios API:Total Composition 7.9E⁻⁵ 1.6E⁻⁴2.4E⁻⁴ 3.2E⁻⁴ 4.7E⁻⁴ 1.6E⁻⁴ 3.2E⁻⁴ 2.4E⁻⁴ PEO:Gelatin 0.109 0.094 0.1200.137 0.114 0.099 0.109 0.117 PEO:Plasticizer 0.145 0.125 0.155 0.1690.151 0.131 0.146 0.149 Gelatin:Plasticizer 1.320 1.325 1.286 1.2291.329 1.321 1.330 1.267

Example 6

Exemplary soft lozenges comprising fluticasone can be prepared by rotarydie encapsulation using compositions shown in Tables 15-16 with twodosage strengths: 0.5 mg or 1.0 mg. The weight of the fill is 2000 mgand the shell is 1162.7 mg. The total weight of the soft lozenge is3162.7 mg. After drying, the final mass of the soft lozenge is about2869.5 mg. Accordingly, about 293.2 mg of water is evaporated duringdrying (˜9.3% water lost).

TABLE 15 Exemplary Soft Lozenge Fill Composition 0.5 mg API 1.0 mg APIMass (mg) Percent Wt (%) Mass (mg) Percent Wt (%) Ingredient Gelatin,150 Bloom 150 7.5 150 7.5 Polyethylene Oxide, 7,000,000 60.0 3.0 60.03.0 MW (e.g., Polyox ® WSR-303) Glycerol 150 7.5 150 7.5 Citric Acid20.0 1.0 20.0 1.0 Maltitol (75% solution; e.g., 1154.7 57.7 1154.2 57.2Lycasin ® 80/55) Xylitol (e.g., Xylisorb 300 ®) 85.0 4.3 85.0 4.3Sucralose 5.8 0.3 5.8 0.3 Polysorbate 80 (e.g., Tween ® 80) 14.0 0.714.0 0.7 Water 360 18.0 360 18.0 Fluticasone propionate 0.50 0.025 1.00.050 TOTAL 2000 100.0% 2000 100.0% Subcomponent Totals Film-formingPolymer 150.0 7.5 150.0 7.5 Release Polymer 60.0 3.0 60.0 3.0Plasticizer 150.0 7.5 150.0 7.5 pH Modifier 20.0 1.0 20.0 1.0 Sweetener1245.5 62.3 1245.0 62.3 Solubilizing Agent 14.0 0.7 14.0 0.7 Solvent360.0 18.0 360.0 18.0 API 0.50 0.025 1.00 0.05 Relational RatiosAPI:Total Fill Composition 0.00025 0.00025 0.0005 0.0005 PEO:Gelatin 0.40.4 0.4 0.4 PEO:Plasticizer 0.4 0.4 0.4 0.4 Gelatin:Plasticizer 1.0 1.01.0 1.0

TABLE 16 Exemplary Soft Lozenge Shell Composition Percent Wt PercentMass (mg) (%) Mass (mg) Wt (%) Ingredient Gelatin, 150 Bloom 219.9 18.9219.9 18.9 Gelatin, 100 Bloom 149.9 12.9 149.9 12.9 Gelatin Hydrolysate27.7 2.4 27.7 2.4 Glycerol 264.6 22.8 264.6 22.8 Citric Acid, Anhydrous6.3 0.54 6.3 0.54 Maltitol (75% solution; 161.7 13.9 163.7 14.1 e.g.,Lycasin ® 80/55) Xylitol (e.g., Xylisorb 29.1 2.5 29.1 2.5 300 ®)Sucralose 2.4 0.21 2.4 0.21 Water 286.6 24.7 286.6 24.7 Titanium Dioxide12.5 1.1 12.5 1.1 Coloring (FD&C dyes) 0.02 0.0017 0 0 Flavoring (e.g.,cherry) 2.0 0.17 0 0 TOTAL 1162.7 100.0% 1162.7 100.0% SubcomponentTotals Film-forming Polymer 397.5 34.2 397.5 34.2 Plasticizer 264.6 22.8264.6 22.8 pH Modifier 6.3 0.5 6.3 0.5 Sweetener 193.2 16.6 195.2 16.8Solvent 286.6 24.6 286.6 24.6 Excipients 14.5 1.2 12.5 1.1 RelationalRatios Gelatin:Plasticizer 1.5 1.5 1.5 1.5

TABLE 17 Exemplary Soft Lozenge Total Composition Percent Percent Mass(mg) Wt (%) Mass (mg) Wt (%) Ingredient Gelatin, 150 Bloom 369.9 11.7369.9 11.7 Gelatin, 100 Bloom 149.9 4.7 149.9 4.7 Gelatin hydrolysate27.7 0.9 27.7 0.9 Polyethylene oxide, 60.0 1.9 60.0 1.9 7,000,000 MW(e.g., Polyox ® WSR-303) Glycerol 414.6 13.1 414.6 13.1 Citric Acid 26.30.8 26.3 0.8 Maltitol (75% 1316.4 41.6 1317.9 41.7 solution; e.g.,Lycasin ® 80/55) Xylitol 114.1 3.6 114.1 3.6 Sucralose 8.2 0.3 8.2 0.3Polysorbate 80 14.0 0.4 14.0 0.4 Water 646.6 20.4 646.6 20.4 Fluticasone0.5 0.016 1.0 0.032 propionate Titanium dioxide 12.5 0.4 12.5 0.4Coloring 0.02 0.0006 0.0 0 (FD&C dyes) Flavoring 2.0 0.1 0 0 (e.g.,cherry) TOTAL 3162.7 100.0% 3162.7 100.0% Subcomponent TotalsFilm-forming 547.5 17.3 547.5 17.3 Polymer Release Modifier 60.0 1.960.0 1.9 Plasticizer 414.6 13.1 414.6 13.1 pH Modifier 26.3 0.8 26.3 0.8Sweetener 1438.7 45.5 1440.2 45.5 Solubilizing Agent 14.0 0.4 14.0 0.4Solvent 646.6 20.4 646.6 20.4 API 0.5 0.016 1.0 0.032 Excipients 14.50.5 12.5 0.4 (opacifier, coloring, flavoring) Relational RatiosAPI:Total 0.00016 0.00016 0.00032 0.00032 PEO:Gelatin 0.11 0.11 0.110.11 PEO:Plasticizer 0.14 0.14 0.14 0.14 Gelatin:Plasticizer 1.32 1.321.32 1.32

Example 7 Manufacturing Process

The soft lozenge compositions described herein were manufacturedaccording to the following processes:

the matrix fill composition is prepared by:

-   (a) combining gelatin, glycerol, and water and maintaining the    mixture at least about 65° C. for at least 5 minutes; adding    maltitol syrup to create a fill gel solution;-   (b) separately, combining water, xylitol, sucralose, and citric acid    together to create a fill sweetener solution;-   (c) separately, combining the active pharmaceutical ingredient (API)    and polysorbate 80;-   (d) combining the API and polysorbate 80 with the fill sweetener    solution to create an API solution;-   (e) combining the API solution and the fill gel solution;-   (f) further mixing the combined API and fill gel solution at least    about 65° C. for at least 5 minutes;-   (g) slowly introducing solid polyethylene oxide into the combined    API and fill gel solution and mixing and deaerating at least about    65° C. for at least 5 minutes to create a matrix fill composition;    the shell gel mass is prepared by:-   (h) combining gelatins, glycerol, and water and maintaining the    mixture at least about 65° C. for at least 5 minutes; adding    maltitol syrup to create a shell gel solution;-   (i) separately, combining water, xylitol, sucralose, and citric acid    together to create a shell sweetener solution;-   (j) combining the shell sweetener solution and shell gel solution    and mixing the combined shell sweetener and shell gel solution at    least about 65° C. for at least 5 minutes to create a gel mass; and

the soft lozenge is prepared by:

-   (k) casting the shell gel mass into shell films or ribbons using    heat-controlled drums or surfaces;-   (l) injecting the matrix fill solution between the shell ribbons,    and creating soft lozenges using rotary die technology.

Example 8

Soft lozenges as described in Tables 15-17 comprising 1 mg offluticasone propionate were manufactured and packaged in 30-count HDPEbottles and stored at 30° C. and 65% relative humidity or 40° C. and 75%relative humidity for stability testing. Samples were evaluated at2-weeks, 1-month, and 2-months after packaging; results are shown inTables 18-20.

TABLE 18 Stability and Disintegration after storage at 40° C. and 75%relative humidity Test Specification⁽¹⁾ Initial 2 weeks 1 month PhysicalDescription White, opaque, pillow Pass Pass Pass shape soft gelatinlozenge Physical Evaluation Passes visual quality Pass Fail (stickingFail (sticking/mis- inspection: lozenges) shaped lozenges)Shell/Color/Print/Shape: meets requirements for abnormalities in capsuleshell, capsule seams, color consistency, print, and misshapen units,Sticking/Package Integrity: meets requirements for sticking, nesting,bricking, and package integrity. Assay 90.0-110.0% of label 96.7% oflabel 98.8% of label 96.1% of label claim (0.9-1.1 mg/ claim (1.0 mg/claim (1.0 mg/ claim (1.0 mg/ lozenge) lozenge) lozenge) lozenge)Degradation Report Results EP Impurity A = EP Impurity A = EP Impurity A= Products (method 1) ND⁽²) ND⁽²) ND⁽²) USP Impurity A = USP Impurity A= USP Impurity A = ND ND ND EP Impurity F = EP Impurity F = EP ImpurityF = ND ND ND RRT 1.23 = ND RRT 1.23 = ND RRT 1.23 = ND Total (methods 1Total (methods 1 Total (methods 1 and 2) = NR⁽³⁾ and 2) = NR⁽³⁾ and 2) =NR⁽³⁾ Degradation Report Results EP Impurity H = EP Impurity H = EPImpurity H = Products (method 2) NR⁽³⁾ NR⁽³⁾ NR⁽³⁾ Disintegration ReportResults 39:32, 40:15, 33:00, 33:00, 35:00, 35:00, (minutes:seconds)40:24, 40:30, 35:00, 35:00, 38:00, 38:00, 40:44, 41:51 35:00, 35:0038:00, 40:00 Microbial Limits Total Plate Count - Total Plate Count: NotScheduled Not Scheduled NMT 1000 cfu/g <10 cfu/g Yeast & Mold - NMTYeast & Mold: <10 cfu/g 100 cfu/g E. coli: Absent E. coli - AbsentSalmonella: Absent Salmonella - Absent S. aureus: Absent S. aureus -Absent P. aeruginosa: P. aeruginosa - Absent Absent ⁽¹⁾Use currentversion of method or compendium. ⁽²⁾None detected. ⁽³⁾Not reported(reporting limit = 0.05%).

TABLE 19 Stability and Disintegration after storage at 40° C. and 75%relative humidity Test Specification⁽¹⁾ Initial 2 months PhysicalDescription White, opaque, pillow Pass Pass shape soft gelatin lozengePhysical Evaluation Passes visual quality Pass Fail (sticking &misshapen inspection: lozenges) Shell/Color/Print/Shape: meetsrequirements for abnormalities in capsule shell, capsule seams, colorconsistency, print, and misshapen units. Sticking/Package Integrity:meets requirements for sticking, nesting, bricking, and packageintegrity. Assay 90.0-110.0% of label 96.7% of label claim (1.0 mg/97.9% of label claim (1.0 mg/ claim (0.9-1.1 mg/ lozenge) lozenge)lozenge) Degradation Report Results EP Impurity A = ND⁽²) EP Impurity A= ND⁽²) Products (method 1) USP Impurity A = ND USP Impurity A = ND EPImpurity F = ND EP Impurity F = ND RRT 1.23 = ND RRT 1.23 = ND Total(methods 1 and 2) = Total (methods 1 and 2) = NR⁽³⁾ NR⁽³⁾ DegradationReport Results EP Impurity H = NR⁽³⁾ EP Impurity H = NR⁽³⁾ Products(method 2) Disintegration Report Results 39:32, 40:15, 40:24, 36:00,38:00, 38:00, 41:00, 41:00, (minutes:seconds) 40:30, 40:44, 41:51 48:00Microbial Limits Total Plate Count - Total Plate Count: <10 cfu/g NotScheduled NMT 1000 cfu/g Yeast & Mold: <10 cfu/g Yeast & Mold - NMT E.coli: Absent 100 cfu/g Salmonella: Absent E. coli - Absent S. aureus:Absent Salmonella - Absent P. aeruginosa: Absent S. aureus - Absent P.aeruginosa - Absent ⁽¹⁾Use current version of method or compendium.⁽²⁾None detected. ⁽³⁾Not reported (reporting limit = 0.05%).

TABLE 20 Stability and Disintegration after storage at 30° C. and 65%relative humidity Test Specification⁽¹⁾ Initial 2 weeks 1 month PhysicalWhite, opaque, pillow Pass Pass Pass Description shape soft gelatinlozenge Physical Passes visual quality Pass Pass Pass Evaluationinspection: Shell/Color/Print/Shape: meets requirements forabnormalities in capsule shell, capsule seams, color consistency, print,and misshapen units. Sticking/Package Integrity: meets requirements forsticking, nesting, bricking, and package integrity. Assay 90.0-110.0% oflabel 96.7% of label 97.2% of label 97.7% of label claim (0.9-1.1 mg/claim (1.0 mg/ claim (1.0 mg/ claim (1.0 mg/ lozenge) lozenge) lozenge)lozenge) Degradation Report Results EP Impurity A = EP Impurity A = EPImpurity A = Products (method ND⁽²) ND⁽²) ND⁽²) 1) USP Impurity A = USPImpurity A = USP Impurity A = ND ND ND EP Impurity F = EP Impurity F =EP Impurity F = ND ND ND RRT 1.23 = ND RRT 1.23 = ND RRT 1.23 = ND Total(methods 1 Total (methods 1 Total (methods 1 and 2) = NR⁽³⁾ and 2) =NR⁽³⁾ and 2) = NR⁽³⁾ Degradation Report Results EP Impurity H = EPImpurity H = EP Impurity H = Products (method NR⁽³⁾ NR⁽³⁾ NR⁽³⁾ 2)Disintegration Report Results 39:32, 40:15, 30:00, 30:00, 32:00, 32:00,(minutes:seconds) 40:24, 40:30, 32:00, 33:00, 35:00, 35:00, 40:44, 41:5133:00, 33:00 35:00, 35:00 Microbial Limits Total Plate Count - NMT TotalPlate Count: Not Scheduled Not Scheduled 1000 cfu/g <10 cfu/g Yeast &Mold - NMT 100 cfu/g Yeast & Mold: <10 cfu/g E. coli - Absent E. coli:Absent Salmonella - Absent Salmonella: Absent S. aureus - Absent S.aureus: Absent P. aeruginosa - Absent P. aeruginosa: Absent ⁽¹⁾Usecurrent version of method or compendium. ⁽²⁾None detected. ⁽³⁾Notreported (reporting limit = 0.05%).

Example 9

A single-dose, randomized, open-label, crossover, comparativebioavailability and placebo-controlled, double-blind taste-test study offluticasone 1 mg lozenge and Flovent® HFA 220 μg (swallowed and inhaled)was performed in healthy male and female volunteers under fastingconditions.

The primary objective of this pilot study was to estimate theintrasubject variability of, and to compare the bioavailability offluticasone administered via a fluticasone 1 mg lozenge and Flovent® HFA220 μg, swallowed and inhaled (GlaxoSmithKline) in healthy male andnon-pregnant female volunteers under fasting conditions.

The secondary objective of this study was to evaluate the taste of thefluticasone and placebo lozenges.

The study was designed as a single-dose, randomized, four-period,three-sequence (comparative BA) and two-sequence (taste test),five-treatment (2 treatments for taste test and 3 treatments forcomparative BA), combined comparative bioavailability and double-blindtaste-test study.

Twenty-four (24) subjects were enrolled made up of healthy, non-smoking(for at least 6 months prior to first study drug administration), maleand non-pregnant female volunteers, between 18 and 65 years, with a bodymass index (BMI) within 18.5-29.9 kg/m², inclusive.

The specific drugs tested were (a) Fluticasone Lozenge 1 mg (Banner LifeSciences), (b) Flovent® HFA 220 mcg, Inhalation Aerosol (GlaxoSmithKlineNC) and (c) a placebo lozenge, to evaluate the taste difference betweenthe placebo and the Fluticasone lozenge 1 mg.

A taste test study was performed by administering both the test drug 1,1 mg Fluticasone Lozenge (Banner Lifesciences) and the placebo lozenge.

A comparative bioavailability study was performed using (a) the testdrug Fluticasone Lozenge 1 mg (Banner Life Sciences) or a firstreference drug (R1), 4×220 μg, inhalation aerosol (for oral ingestion)or a second reference drug (R2) 4×220 mcg, inhalation aerosol (toinhale) in each study period.

Safety monitoring will be conducted and the duration of confinement willbe broken up into four periods of time. Period 1 was from at least tenhours prior to, and until at least eight hours after the first doseadministration, for a total of at least 18-hours for study Period 1.Periods 2, 3 and 4 was from at least ten hours prior to dosing until atleast 24-hours post-dose, for a total of at least 34-hours for each ofthree study periods with a minimum of at least four days between eachdosing. Vital signs (blood pressure and heart rate) were measured foreach period. Period 1 vital signs will be measured at pre-dose and atone, three and eight hours after the first dose. Vital signs for theremaining time periods was measured at pre-dose and at one, three, five,eight and 24 hours after the first dose.

The Principal Investigator/Sub-Investigator was present fromapproximately 30-minutes prior to dosing until at least four hours afterthe last subject was dosed in each study period. The PrincipalInvestigator/Sub-Investigator remained on-call throughout the durationof the study.

All blood samples were collected in a 6 mL, pre-chilled, sodiumfluoride/potassium oxalate Vacutainer® at the following time intervalsfor Periods 2, 3 and 4: 0, 0.083, 0.167, 0.333, 0.5, 0.75, 1, 1.25, 1.5,1.75, 2, 3, 4, 6, 8, 16, 24 and 48-hours post-dose in each study period.

Approximately 353 mL of blood, including ˜29 mL for pre- and post-studyprocedures were drawn. Plasma samples were assayed for fluticasone usinga validated analytical method according to the principles of GoodLaboratory Practice. The Analysis of Variance (ANOVA) for ln-transformedAUC_(0→τ), AUC_(0→τ), and C_(max), and untransformed T_(max), λ andt_(1/2). T_(max) was also analyzed using an additional non-parametrictest (Wilcoxon test). The 90% confidence intervals (CI) for theTest/Reference ratios of geometric means for AUC_(0→τ), AUC_(0→∞), andC_(max) were calculated based on the least square means (LSMEANS) andESTIMATE of the ANOVA.

Palatability scores were calculated for the lozenges and summarized withdescriptive statistics. Within-subject paired differences incharacteristic scores between placebo and test lozenges were analyzedusing non-parametric Wilcoxon Signed-Rank tests if data permitted.

Taste-Test Study—Period 1

This part of the study was a single-dose, randomized, double-blind,cross-over, single-period, two-sequence, two-treatment taste study offluticasone lozenge 1 mg (Banner Life Sciences) and placebo lozenge(Banner Life Sciences). In this treatment period, 24 healthy, adultnon-smoking (for at least 6 months prior to first drug administration)male and non-pregnant female volunteers were administered 1×1 mgfluticasone propionate lozenge and 1 AUG_(0→∞) placebo lozenge underfasting conditions.

Comparative Bioavailability Study—Periods 2, 3 and 4

This was a single-dose, randomized, open-label, 3-way crossover,three-period, three sequence, three-treatment, single-center,comparative bioavailability study of fluticasone lozenge 1 mg andFlovent® HFA 220 μg, both swallowed and inhaled (GlaxoSmithKline). In 3separate treatment periods, the 24 healthy, adult non-smoking (for atleast 6 months prior to first drug administration) male and non-pregnantfemale volunteers were administered 1×1 mg fluticasone propionatelozenge, 4×220 μg inhalation aerosol to swallow or 4×220 μg inhalationaerosol to inhale under fasting conditions.

There was at least a 4-day washout period between the study periods. Thewashout period of at least 4 days was estimated to be adequate inavoiding potential carry-over effects of the preceding treatments. Bloodsamples were collected in Period 2, Period 3 and Period 4, at pre-doseand at 0.083, 0.167, 0.333, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6,8, 16, 24 and 48 hours post dose in each study period.

Study Duration and Confinement Period 1

Subjects were confined to the clinic from at least 10-hours prior to,and until at least 8-hours after the first dose, for a total of at least18-hours for study Period 1.

Period 2, Period 3 and Period 4

Subjects were confined to the clinic from at least 10 hours prior todosing until at least 24-hours post-dose, for a total of at least34-hours for each study period. Subjects were required to return to theclinical facility for the 48-hour blood draw in study Period 2, Period 3and Period 4.

Randomization and Blinding

In this study, assignment of two separate treatment groups(randomization scheme) for taste test and comparative BA was generatedby a computer program designed and run in SAS® Version 9.4.

Comparative Bioavailability Study

The comparative bioavailability study was open-label, and subjects aswell as the study staff will were not blinded to the randomization. Thebioanalytical laboratory did not have access to the randomization schemeuntil the bioanalytical analysis is complete. To avoid any studyevaluation bias, the taste test study was double-blinded, where thefluticasone lozenge and its matching placebo were blinded to bothsubjects and clinic staff in charge of reviewing and evaluating adverseevents and safety.

In the taste-test portion of the study, un-blinding was only permittedin case of an emergency involving a subject where it was necessary toknow which treatment the subject received prior to the subject receivingmedical aid. The investigator and the Sponsor had the ability toun-blind the treatment assignment for subjects enrolled in the study.

Subjects who met the eligibility criteria were randomly assigned equallyinto both of the following treatment groups:

Period 1: Two Sequence Groups Period 1 Sequence 1 T P Sequence 2 P TPeriods 2, 3 and 4: Three Sequence Groups Period 2 Period 3 Period 4Sequence 1 T R1 R2 Sequence 2 R1 R2 T Sequence 3 R2 T R1 T = fluticasonelozenge; P = placebo lozenge; R1 = Flovent HFA ingestion; R2 = FloventHFA inhalation

Each subject was scheduled to receive a total of five treatments by theend of the study.

Dosing

Subjects took their assigned formulation after a fast of at least10-hours at their scheduled time point.

Period 1 (Taste-Test)

The subject received the fluticasone propionate ‘test’ drug lozenge (T)and the placebo lozenge (P) approximately 2 hours apart. The subject wasasked to complete a questionnaire in 3 minutes after administering thelozenge for the initial-taste assessment, and after the lozengecompletely disintegrated for after-taste assessment, to evaluate thetaste characteristics of the lozenge. Disintegration time should havebeen documented by clinic staff. The subject was NOT to be informedwhether the lozenge had active drug or placebo.

First Dose Administration

Subjects were asked to rinse their mouth with 20 mL of ambienttemperature water for approximately five seconds and swallow that waterprior to lozenge administration. Subjects were instructed to swallowsaliva before dosing. Subsequently, staff placed the lozenge directly onthe subject's tongue, and asked the subject to close his/her mouth in anatural way, without swallowing, chewing, biting or breaking thelozenge, to permit complete lozenge disintegration. If the subjectchewed or swallowed or moved the study drug before it was completelydissolved, the subject was removed from the study. After subjectsindicated complete disintegration of the lozenge (confirmed by visualinspection) they were allowed to swallow. Dosing time was set to thetime the lozenge was placed on the subject's tongue. Subjects wereinstructed to inform study staff when they believed that the lozenge wascompletely disintegrated.

Visual inspection of the lozenge was conducted by the study staff everytwo minutes until either disintegration was noted or until the subjectalerted the study staff to complete disintegration of the lozenge byraising their hand.

Following completion of the after taste assessment for the first dose,subjects were served two cookies and 50 mL of orange juice. Subjectswere also provided with 60 mL of water to rinse the mouth and swallowthat water.

Second Dose Administration

Subject fasted for one hour before the second lozenge administration.Subject rinsed the mouth with 20 mL of water for approximately fiveseconds and swallowed that water prior to lozenge administration.Subjects swallowed saliva before dosing. Staff placed the lozengedirectly on the subject's tongue, and asked the subject to close his/hermouth in a natural way, without swallowing, chewing, biting or breakingthe lozenge, permitting complete lozenge disintegration. After subjectsindicated complete disintegration of the lozenge (confirmed by visualinspection) they were allowed to swallow. After completion of theafter-taste assessment for the second lozenge, 60 mL of water wasprovided to rinse the mouth and subjects swallowed the water.

Following the administration of each lozenge, hands and mouth werechecked in order to confirm the consumption.

In the taste test questionnaire, the taste was categorized using aspecific scoring grid with values from 1-5 for bitterness, sweetness,mouth feel (grittiness), flavor, and overall acceptability; adapted fromReddy et al, “Evaluation Study of Oral Disintegrating Tablets by HumanVolunteers.” Internat. J. Pharm. Science Res. 1(8):326-346 (2010), whichis incorporated by reference herein for such teachings. Three minutesafter placing the lozenge on the tongue, the subject recorded theirfeedback in the table based on a scoring grid. The taste scoring, oncecompleted, was taken from the subject.

Once the lozenge has completely disintegrated, the subject recordedtheir feedback again in the questionnaire based on the scoring grid.When completing the second scoring grid, subjects were not permitted tosee their prior responses.

Period 2, Period 3 and Period 4—Lozenge Administration (Test)

The subjects were instructed by the designated study staff to movehis/her tongue around the mouth (front and back part of gums, teeth andpalate) two times and document any signs of oral irritation and/or anymouth, tongue or gum ulcer(s) were investigated. Just prior to drugadministration, each subject rinsed his/her mouth for approximately 5seconds with approximately 20 mL of room temperature water, and thenswallowed the water. Subjects were instructed to swallow saliva beforedosing. Subsequently, staff placed the lozenge directly on the subject'stongue, and asked the subject to close his/her mouth in a natural way,without swallowing, chewing, biting or breaking the lozenge, in order topermit complete lozenge disintegration. If the subject chewed, swallowedor moved the study drug before it was completely dissolved, the subjectwas removed from the study. After subjects indicated completedisintegration of the lozenge (confirmed by visual inspection) they wereallowed to swallow. Dosing time was set to the time the lozenge wasplaced on the subject's tongue. Subjects were instructed to inform studystaff when they believed that the lozenge had completely disintegrated.

Visual inspection of the lozenge was conducted by the study staff every2-minutes until either disintegration was noted or until the subjectalerted the study staff to complete disintegration of the lozenge byraising their hand. Subjects should refrain from talking until completedisintegration of the lozenge is verified by study staff.

The study staff recorded the actual time of lozenge placement and theactual time of disintegration. Subjects were instructed to notify studystaff if the lozenge was accidentally swallowed before it was completelydisintegrated. Study staff recorded the time the lozenge was swallowed.

Following the administration of the lozenge, hands and mouth werechecked in order to confirm the consumption. Following completedissolution of the lozenge, the subject rinsed his/her mouth with 60 mLof water and then swallowed the water.

The subject was asked to move his/her tongue around the mouth (front andback part of gums, teeth and palate) two times.

Reference Drug (R1—FLOVENT Ingested)

Just prior to drug administration, each subject rinsed his/her mouth forapproximately 5 seconds with approximately 20 mL of room temperaturewater, and then swallowed this water. Subjects were assigned to takefour inhalations, swallowed approximately 30 seconds apart. Followingthe fourth and final inhalation/swallow, the subject rinsed his/hermouth with 60 mL of water and then swallowed the water.

Reference Drug (R2—FLOVENT Inhaled)

The reference drug was delivered using a “spacer” (also known asaerosol-holding chambers, add-on devices and spacing devices).

Just prior to drug administration, each subject rinsed his/her mouth forapproximately 5 seconds with approximately 20 mL of room temperaturewater, and then will swallowed this water. Subjects were assigned totake four inhalations, 30 seconds apart. Following the fourth and finalinhalation/swallow, the subject rinsed his/her mouth with 60 mL of waterand then swallowed the water.

Pharmacokinetic and Palatability Analysis Data Set

Two populations were defined for the final PK and statistical analysisas follows:

-   -   1. The PK population includes all subjects for whom PK can be        determined following a fluticasone (T) dose and at least 1        reference dose (R1 or R2).        -   2. The full population is comprises of all subjects who            received at least one study dose either placebo or test            lozenge. This population was also used for the Taste Test            analysis.

Data from subjects who were dismissed/withdrawn or who withdrew wasevaluated by a BPSI PK specialist and/or the Sponsor for inclusion inthe PK and statistical analysis. Subjects with emesis within 4-hourspost-dose from period 2, period 3, and period 4, may have been includedin the PK analysis, at the discretion of the pharmacokinetic scientist.All other subject data were reported separately. Non-compliant subjectdata were not included in the PK population, but will be reportedseparately.

Analysis of Data

Pharmacokinetic and statistical analysis was performed on all data fromall subjects in the PK population. Any bioanalytical and/or PK data fromsubjects not included in the PK population but in the full populationwill be reported separately.

The PK and/or statistical analyses outlined in this protocol may bealtered with appropriate justification.

Pharmacokinetic Analysis

Pharmacokinetic parameters were calculated using non-compartmentalanalysis (NCA) method. The following PK parameters were estimated (wherepossible) for fluticasone:

-   -   C_(max) The maximal observed plasma concentration.    -   T_(max) Time when the maximal plasma concentration is observed.    -   AUC_(0→τ) Area under the concentration-time curve from time zero        until the last measurable concentration or last sampling time t,        whichever occurs first. AUC_(0→τ) is estimated using the        trapezoidal method.    -   AUC_(0→∞) Area under the concentration-time curve from time zero        to infinity, calculated as AUG_(0→τ)+C_(last)/κ, where C_(last)        is the last measurable concentration.    -   λ Terminal elimination rate constant, estimated by linear        regression analysis of the terminal portion of the        ln-concentration vs. time plot.    -   t_(1/2) Terminal elimination half-life, estimated as ln(2)/κ.

During PK and statistical analyses, drug concentrations below the lowerlimit of quantitation (BLQ) of an assay were considered as zero exceptwhen they occurred following the appearance of quantifiableconcentration in the time course; thereafter they were considered asmissing during PK calculations and estimations.

Missed samples and non-reportable concentrations (e.g. quantity notsufficient) from the analytical laboratory were treated as missing inthe PK analysis.

The κ, t_(1/2), and AUG_(0→∞) parameters were estimated for plasmaconcentration-time profiles where the terminal linear phase was notclearly defined, (i.e. the R² of the terminal linear regression is not≧0.700).

Statistical Analysis

The PK and statistical analysis was performed at BPSI using SAS® Version9.4.

Descriptive statistics (min, max, median, mean, standard deviation andcoefficient of variability) of all PK parameters in the PK populationwere provided for fluticasone for the Test and Reference products.

ANOVA including sequence, subjects nested within sequence, period andtreatment were performed on the ln-transformed data for AUC_(0→τ),AUC_(0→∞), and C_(max) and on the untransformed data for T_(max), λ, andt_(1/2). T_(max) were analyzed using an additional non-parametric test(Wilcoxon test).

The 90% CI of the Test/Reference ratios of geometric means forAUC_(0→τ), AUC_(0→∞), and C_(max) were calculated based on the LSMEANSand ESTIMATE of the ANOVA.

The following statistical comparisons were performed:

-   -   Treatment T vs. Treatment R1    -   Treatment T vs. Treatment R2    -   Treatment R1 vs Treatment R2

Palatability Analyses

Using the full population, palatability of the fluticasone and placebolozenges was measured as described by Reddy et al, Internat. J. Pharm.Science Res. 1(8):326-346 (2010), incorporated by reference herein forthese specific teachings. The analysis differs marginally because thisstudy is evaluating only two lozenges (Test and Placebo). Initial andpost-dissolution palatability was evaluated on four characteristics:bitterness, sweetness, mouth feel, and pleasantness of flavor.Descriptive statistics of the ordinal characteristic scores (1-5) werepresented for the placebo and fluticasone lozenges; the statisticsincluded frequency distributions of the scores, as well as summarystatistics (mean, standard deviation.) of the scores. Within-subjectpaired differences between Placebo and Test scores were evaluated usingnonparametric Wilcoxon Signed-Rank tests, assessing the null hypothesisof zero difference in scores.

Additional statistical tests were performed as necessary (e.g., initialvs. post-dissolution scores).

Example 10

Summary of pharmacokinetic parameters from the bioavailability studydescribed in Example 10 are shown in Tables 21 and 22. Plots of meanfasting plasma concentrations versus time are shown in FIG. 1. Thequantity of systemic Test fluticasone provided by the pharmaceuticalcompositions described herein is very low ˜10 pg/mL and is about30-times lower than the Reference.

TABLE 21 Mean Fasting Plasma Concentrations for Fluticasone propionateAfter Dosing Test Reference Conc. Conc. Time (h) (pg/mL) Std Dev.(pg/mL) Std Dev. Pre-dosing 0.07 0.28 0 0 0.083 0.08 0.32 38.26 56.550.167 0.09 0.32 59.67 74.26 0.333 0.35 0.72 110.88 108.34 0.5 1.59 1.87180.55 177.48 0.75 3.41 2.46 217.10 193.06 1 5.64 3.81 256.39 233.541.25 7.54 4.65 272.78 223.70 1.5 9.15 5.26 287.90 224.13 1.75 9.95 5.34298.25 229.88 2.0 10.43 5.76 308.25 245.92 3.0 10.14 5.67 284.04 218.944.0 8.73 4.82 270.80 212.48 6.0 5.85 2.62 183.73 145.34 8.0 4.60 2.22166.96 136.21 16.0 2.58 1.12 69.52 62.88 24.0 1.91 1.12 42.57 38.86 48.00.91 1.18 10.78 9.31 N = 14 subjects

TABLE 22 Summary of Comparative Bioavailability Analysis for Fluticasone1 mg Lozenge Single-dose, randomized, open-label, crossover, comparativebioavailability Geometric Mean *Arithmetic Mean (% CV) AUC_(0→τ)AUC_(0→∞) C_(max) AUC_(0→τ)/ Sample (pg · h/mL) (pg · h/mL) (pg/mL)T_(max) (h)* t_(1/2) (h)* λ (1/h)* AUC_(0→∞) ^(†) Reference 1523.191533.60 121.50 1.76 12.06 0.0591 0.9551 (R) 3852.78 4045.56 322.17(1.00-4.08) (17.05) (17.96) (1.49) (81.51) (81.51) (79.75) Test (T)108.91 154.56 9.06 2.00 0.0604 15.39 0.7532 125.51 157.69 10.86(1.75-3.00) (54.01) (56.78) (13.79) (58.11) (60.75) (53.39) Ratio ofGeometric 90% Confidence Intra-subject CV Means (T:R) Interval (%) Test(T) AUC_(0→τ) 7.15 4.64-11.02 55.54 AUC_(0→∞) 10.08 6.04-16.83 63.11C_(max) 7.46 4.66-11.95 61.25 Reference (R): Flovent ® HFA 220 μg(fluticasone propionate 220 μg; Inhalation Aerosol) (GlaxoSmithKline)Test (T): Fluticasone propionate 1.0 mg lozenge (Banner Life Sciences);see Tables 15 and 17 *Arithmetic mean (% CV) only ^(†)Median and rangeonly

Example 11 Palatability Data Assessment

The nonparametric Wilcoxon Signed-Rank Test showed that there were notany statistically significantly differences for scores of bitterness,sweetness, mouth feel, and flavor between Test and Placebo groups forboth initial-taste assessment phase and post-dissolution tasteassessment phase, respectively. These results show that patients did notdetect and difference in taste associated with the fluticasoneformulation in lozenge dosage form as described herein as compared tothe placebo lozenge lacking fluticasone.

TABLE 23 Summary of P-Values Using Wilcoxon Signed-Rank Test forDifferences between Placebo and Test Scores Evaluation Taste TestP-Value Significant Bitter Initial 0.8234 No Sweet Initial 0.2100 NoMouth Feel Initial 0.9727 No Flavor Initial 0.6292 No BitterPost-dissolution 0.8750 No Sweet Post-dissolution 0.2051 No Mouth FeelPost-dissolution 0.4465 No Flavor Post-dissolution 0.2432 No Test:Fluticasone Propionate Lozenge, 1.0 mg; Lot No: 147000651A; (Banner LifeSciences LLC) Placebo: Fluticasone Propionate Lozenge Placebo Lot No:147000655A; (Banner Life Sciences LLC)

Example 11

A non-controlled oral dissolution study was performed where fivesubjects were given the lozenge of Examples 15 and 17. Subjects weregiven no instructions or restrictions other than to communicate whentheir lozenge was completely dissolved without chewing or biting thelozenge. Subjects were provided the lozenge and were asked to place intheir mouth, at which time timing began.

Complete oral dissolution occurred over a range of about 10 to about 15minutes, with an average oral dissolution time of 12.5 minutes.

1. A topical, non-systemic, oral, slow releasing pharmaceuticalcomposition comprising: (a) about 1% to about 5% by mass of one or morerelease modifiers; (b) about 10% to about 60% by mass of one or morefilm-forming polymers; (c) about 5% to about 20% by mass of one or moreplasticizers; and (d) less than 1% by mass of one or more activepharmaceutical ingredients.
 2. The composition of claim 1, furthercomprising: (e) about 0.1% to about 5% by mass of one or more pHmodifiers; (f) about 10% to about 80% by mass of one or more sweeteners;and (g) about 5% to about 30% by mass of one or more solvents.
 3. Thecomposition of claim 1, further comprising: (h) one or more opacifiers,coloring agent, flavoring, thickening agents or combinations thereof;(i) one or more solubilizing agents; and (j) one or more second activepharmaceutical ingredients.
 4. The composition of claim 1, wherein thecomposition comprises a soft lozenge.
 5. The composition of claim 4,wherein the composition orally dissolves within about 10 to about 15minutes upon administration to a subject.
 6. The composition of claim 4,wherein the composition achieves about 50% dissolution in vitro at pH7.4 within about 10 to about 30 minutes.
 7. The composition of claim 4,wherein the composition topically contacts the oral and esophagealmucosa for at least about 1 minute to at least about 45 minutes. 8.(canceled)
 9. The composition of claim 1, wherein the release modifiercomprises polyethylene oxide.
 10. (canceled)
 11. The composition ofclaim 1, wherein the release modifier comprises polyethylene oxidehaving a molecular weight (M_(v)) of about 7,000,000. 12-13. (canceled)14. The composition of claim 1, wherein the plasticizer comprises one ormore of glycerol, sorbitol, mannitol, maltitol, xylitol, or combinationsthereof. 15-18. (canceled)
 19. The composition of claim 1, wherein theactive pharmaceutical ingredient comprises one or more corticosteroids.20-21. (canceled)
 22. The composition of claim 1, wherein the activepharmaceutical ingredient comprises fluticasone or a salt thereof. 23.The composition of claim 1, wherein the active pharmaceutical ingredientcomprises fluticasone propionate.
 24. The composition of claim 1,wherein the composition comprises about 0.025% or about 0.05%fluticasone propionate.
 25. The composition of claim 1, wherein thecomposition comprises about 0.5 mg or about 1.0 mg of fluticasonepropionate. 26-27. (canceled)
 28. A topical, non-systemic oralpharmaceutical composition comprising: (a) about 10% to about 60% bymass of one or more film-forming polymers; (b) about 5% to about 20% bymass of one or more plasticizers; (c) about 0.1% to about 5% by mass ofone or more pH modifiers; (d) about 10% to about 80% by mass of one ormore sweeteners; (e) about 5% to about 30% by mass of one or moresolvents; (g) about 1% to about 5% by mass of one or more releasemodifiers; (h) about 0.1% to about 5% by mass of one or moresolubilizing agents; and (i) about 0.001% to about 1% by mass offluticasone propionate.
 29. The composition of claim 28, furthercomprising (j) about 0.1% to about 50% by mass of one or more thickeningagents.
 30. The composition of claim 28, further comprising a secondactive pharmaceutical ingredient.
 31. The composition of claim 30,wherein the second active pharmaceutical ingredient comprises about 0.5%to about 5% by weight of lidocaine, prilocaine, or a combinationthereof, and the weight percentage of maltitol is reduced accordingly.32. The composition of claim 28, wherein the composition comprises aliquid or solid dosage form.
 33. (canceled)
 34. The composition of claim32, wherein the solid dosage form comprises a soft lozenge.
 35. Thecomposition of claim 34 wherein the composition orally dissolves withinabout 10 to about 15 minutes upon administration to a subject.
 36. Thecomposition of claim 34, wherein the composition achieves 50%dissolution in vitro at pH 7.4 within about 10 to about 30 minutes. 37.The composition of claim 34, wherein the composition topically contactsthe oral and esophageal mucosa for at least about 1 minutes to at leastabout 45 minutes.
 38. The composition of claim 34, wherein thecomposition provides one or more of the following pharmacokineticparameters upon administration to a subject: (a) a mean plasmafluticasone propionate T_(max) of about 1.75 hours to about 3 hours; (b)a mean plasma fluticasone propionate C_(max) of about 8 pg/mL to about11 pg/mL; (c) a mean plasma fluticasone propionate AUC_(0→τ) of about105 pg·h/mL to about 130 pg·h/mL; (d) a mean plasma fluticasonepropionate AUC_(0→∞) of about 150 pg·h/mL to about 160 pg·h/mL; (e) amean fluticasone propionate half-life (t_(1/2)) of about 0.01 h to about0.1 h; or (f) a mean fluticasone terminal elimination rate constant (λ)of about 10 h⁻¹ to about 20 h⁻¹.
 39. The pharmaceutical composition ofclaim 28, wherein the composition is useful for treating a subjectsuffering from one or more of oral or esophageal inflammation,eosinophilic esophagitis, inflammatory bowel disease involving theesophagus, oral lichen planus, aphthous stomatitis, Crohn's disease,esophageal inflammation secondary to caustic/irritant ingestion,recurrent esophageal strictures of any cause and including irritantingestion, pill-induced esophagitis, systemic diseases, congentialdiseases, epidermolysis bullosa, trauma, or post-surgery inflammation.40. A method for treating, retarding the progression of, prophylaxis of,delaying the onset of, ameliorating, or reducing the symptoms of one ormore of esophageal, oral, or buccal inflammation, eosinophilicesophagitis, oral lichen planus, aphthous stomatitis, odynophagia, acidreflux, dysphagia, oral, esophageal or peptic ulcers, heart burn, chestpain, abdominal pain, nausea, vomiting, coughing, sore throat, decreasein appetite, or failure to thrive, comprising administering to a subjectin need thereof the pharmaceutical composition of claim
 28. 41.(canceled)
 42. A method for treating for treating, retarding theprogression of, prophylaxis of, delaying the onset of, ameliorating, orreducing the symptoms of one or more of esophageal oral, or buccalinflammation, eosinophilic esophagitis, inflammatory bowel diseaseinvolving the esophagus, oral lichen planus, aphthous stomatitis,Crohn's disease, esophageal inflammation secondary to caustic/irritantingestion, recurrent esophageal strictures of any cause and includingirritant ingestion, pill-induced esophagitis, systemic diseases,congential diseases, epidermolysis bullosa, trauma, or post-surgeryinflammation comprising administering to a subject in need thereof thepharmaceutical composition of claim
 34. 43. The method of claim 42,wherein administering the composition provides one or more of thefollowing pharmacokinetic parameters: (a) a mean plasma fluticasonepropionate T_(max) of about 1.75 hours to about 3 hours; (b) a meanplasma fluticasone propionate C_(max) of about 8 pg/mL to about 11pg/mL; (c) a mean plasma fluticasone propionate AUC_(0→τ) of about 105pg·h/mL to about 130 pg·h/mL; (d) a mean plasma fluticasone propionateAUC_(0→∞) of about 150 pg·h/mL to about 160 pg·h/mL; (e) a meanfluticasone propionate half-life (t_(1/2)) of about 0.01 h to about 0.1h; or (f) a mean fluticasone terminal elimination rate constant (λ) ofabout 10 h⁻¹ to about 20 h⁻¹.
 44. A pharmaceutical combinationcomprising the composition of claim 28 and one or more additionaltherapeutic compounds.
 45. (canceled)